NEUROVASCULAR MEDICINE - Pursuing Cellular Longevity for Healthy Aging Part 3 ppsx

In addition, adrena-lin released from the C1Ad axons limits and/or inhibits the A5NA neurons, responsible for neural sympathetic activity, by acting at α-2 postsynaptic receptors located

fall) symptoms are seen during relapsing periods Lung metastases are frequently observed Worsening and death cannot be avoided because of liver, pancre-atic, and lung metastases.

Circulating 5-HT arises from the ffi n cells that release it in response to parasympa-thetic drive (Tobe 1974) Although most serotonin is secreted into the intestinal lumen, a fraction reaches portal circulation Serotonin that escapes from uptake

enterochroma-by the liver and lungs is trapped enterochroma-by platelets (Rausch, Janowsky, Risch et al 1985) However, some fraction of serotonin always remains free in the plasma (f5-HT) The normal f5-HT/p5-HT circulating ratio is about 0.5% to 1% This ratio increases during both platelet aggregation and defi cit of platelet uptake (Larsson, Hjemdahl, Olsson et al 1989) Both circulating ace-tylcholine because of hyperparasympathetic activ-ity and circulating dopamine interfere with platelet uptake (De Keyser, De Waele, Convents et al 1988) The increase of f5-HT observed in these circumstances may be exacerbated because indolamine excites 5-HT-3 and 5-HT-4 receptors located at the medul-lary AP (outside the BBB), which is connected with the motor vagal complex (Reynolds, Leslie, Grahame-Smith et al 1989) The increased f5-HT results in a further increase of the peripheral parasympathetic discharge over the enterochromaffi n cells (Bezold–Jarisch refl ex) Such mechanisms explain the hyper-serotonergic storm occurring in carcinoid patients frequently

Patients affected by carcinoid tumors present alternation of clinical syndromes (parasympathetic and adrenal sympathetic predominance) This bipo-lar syndrome depends on the interaction between the medullary DVC and the C1(Ad) nuclei The fact that both systems are under control of the A5(NA) nucleus (responsible for the peripheral neural sympathetic activity) (Fenik, Marchenko, Janssen et al 2002) sug-gests that any neuropharmacological therapy should

be addressed to restore the hierarchical supremacy of the latter nucleus

The immunological investigation of these ents showed a TH-2 profi le (raised levels of TH-2 cytokines IL-6, IL-10, and β-interferon, reduced nat-ural killer (NK) cell cytotoxicity against the K-562 target cells, and reduced CD4/CD8 ratio (lower than 1; normal values ≈2)

pati-An adequate neuropharmacological therapy to enhance neural sympathetic activity and to reduce adrenal sympathetic activity was able to normal-ize clinical, neurochemical, neuroautonomic, and immunological parameters Up to the present, we have successfully treated nine patients affected by the carcinoid syndrome Control periods ranged between 6 months and 7 years No relapses have been observed The treatment is interrupted periodically

explains the CNS–peripheral cascade, which

pro-vokes this type of stress (Jacobs, Heym, Trulson

1981) Prolongation of this behavior triggers the

pro-gressive inhibition of the A6(NA) neurons because

both adrenalin and serotonin are coreleased at this

nucleus from axons arising from the C1(Ad) and the

DR(5-HT) nuclei, respectively In addition,

adrena-lin released from the C1(Ad) axons limits and/or

inhibits the A5(NA) neurons, responsible for neural

sympathetic activity, by acting at α-2 postsynaptic

receptors located at the somatodendritic area of these

neurons (Li, Wesselingh, Blessing 1992; Lechin, van

der Dijs, Benaim 1996a; Fenik, Marchenko, Janssen

et al 2002)

Parasympathetic Predominance

The uncoping stress disorder is caused by two

alterna ting periods: (1) adrenal sympathetic

pre-dominance and (2) parasympathetic prepre-dominance

Neural sympathetic drive is absent in both

circum-stances Raised adrenalin and plasma serotonin

(f5-HT) underlie both alternating periods The

raised f5-HT depends on the maximal serotonin

release from the enterochromaffi n cells excited by

the enhanced parasympathetic drive In addition,

the raised levels of plasma adrenalin observed

dur-ing this uncopdur-ing stress syndrome triggers platelet

aggregation Serotonin arising from platelets is split

to the plasma

Carcinoid Syndrome

Carcinoid syndrome should be included among the

uncoping stress disorders Both adrenal sympathetic

hyperactivity and raised cortisol plasma levels are

observed in these patients (Lechin, van der Dijs,

Orozco et al 2005c) Noradrenaline plasma level

does not rise at the 1-minute orthostasis challenge,

and in addition, the adrenalin plasma levels show

maximal increases through the exercise challenge

The facts that both f5-HT and platelet serotonin

(p5-HT) reach maximal levels during relapsing

periods indicate overactivation of both the

entero-chromaffi n cells and the adrenal gland These cells

are submitted to two opposite neurological stimuli:

parasympathetic (excitatory) and neural sympathetic

(inhibitory) (Tobe, Izumikawa, Sano et al 1976)

The latter is absent during relapsing periods In

addition, enterochromaffi n cells are also present at

both hepatic and pancreatic areas Patients affected

by this type of tumor, present symptomatic and

symptomless alternating periods Gastrointestinal

(diarrhea, vomit, abdominal pain, etc.) and

cardio-vascular (tachycardia, extrasystoles, blood pressure

Cystic Fibrosis and Pancreatic CystsThe two syndromes, cystic fi brosis and pancreatic cysts, are caused by similar autonomic nervous system (ANS) disorder, which allows a common neurophar-macological therapy Six patients affected by pancre-atic cysts and four patients affected by cystic fi brosis have been successfully treated with neuropharma-cological therapy All of them showed an uncoping stress profi le: predominance of adrenal over neural sympathetic activity In addition, all they showed raised levels of p5-HT This latter parameter indicated that all patients secreted higher than normal sero-tonin from the enterochromaffi n cells (Lechin, van der Dijs, Orozco et al 2005d).

The enterochromaffi n cells release serotonin during postprandial periods and during peripheral parasympathetic activity These cells are excited by vagal nerves Serotonin released to the portal vein is taken up by the liver; however, some fraction of this indolamine escapes from liver uptake and reaches the blood stream In addition, it has been demon-strated that serotonergic nerves innervate pancreatic exocrine gland

Overexcited pancreatic exocrine glands secrete

a greater than normal amount of pancreatic juice, which would enhance intraacinar pressure and pro-voke the degeneration of the acinos Thus, pancreatic exocrine glands turn into pancreatic cysts

Our therapeutic strategy was addressed the tion of the parasympathetic activity, which depends

inhibi-on both the excessive adrenal sympathetic and the neural sympathetic activities The ANS unbalance triggered by the absence of the neural sympathetic drive would favor the parasympathetic versus adre-nal sympathetic instability In addition, these patients present positive antipancreatic (++) and antinuclear (+) antibodies when immunologically investigated All immunoglobulins were also raised

Doxepin (25 mg) before bed, clonidine (0, 15 mg) before meals, and propantheline (15 mg) at 10:00 am and 4:00 pm were prescribed Signifi cant clinical, ANS, and immunological improvements were obtai-ned after the fi rst 4-week period and continue up to the present (June 2008)

It may be postulated that pancreatic cyst tion will be favored by factors that overwhelm the pancreatic duct drainage capacity by excessive acinar cell secretion

forma-Several ANS and hormonal factors are involved

in pancreatic exocrine secretion Sympathetic nerves terminate on intrapancreatic blood vessels In addi-tion, inhibition of exocrine secretion may occur in the absence of vascular effects (α-receptor blockade) (Roze, Chariot, Appia et al 1981), suggesting that the catecholamines may act directly on the secretory

every 5 to 6 months (Lechin, van der Dijs, Orozco

et al 2005c; Lechin, van der Dijs 2005c)

Acute Pancreatitis

Acute pancreatitis is a severe and frequently

uncon-trollable disease, which shows an important index

of mortality Severe abdominal pain, vomits, and

disorders of cardiovascular parameters are always

present Usually, these patients are treated at the

intensive care units and the mortality rate is high

In 1992, we published our fi rst clinical report

show-ing the successful therapy of this disease with a

small dose of intramuscularly injected clonidine

(0.15 mg) 2 to 3 times daily (Lechin, van der Dijs,

Lechin et al 1992b) All patients recovered within

the next 48 to 72 hours The amylase plasma levels

become normal after the fi rst clonidine

administra-tion and remain normal further Up to the present,

we have successfully treated more than 100 acute

pancreatitis patients, without any failure (Lechin,

van der Dijs, Lechin et al 1992b, 2002c; Lechin, van

der Dijs 2004b)

We outlined this therapy because we were aware

that clonidine is able to provoke dry mouth

(inhibi-tion of the salivary gland), which parallels

pancre-atic exocrine secretion It is commonly accepted

that both salivary and pancreatic exocrine

secre-tion share a common CNS excitatory mechanism In

addition, it was recently demonstrated that

pancre-atic nerves responsible for the pancrepancre-atic exocrine

secretion depend on the C1(Ad) medullary nuclei

(Roze, Chariot, Appia et al 1981), which are the CNS

nuclei connected to the pancreatic exocrine gland

(Loewy, Haxhiu 1993; Loewy, Franklin, Haxhiu

1994) These fi ndings fi t well with the known fact

that clonidine exerts maximal CNS sympathetic

inhi-bition by acting at the α-2 receptors located at these

nuclei, which are the adrenergic medullary neurons

whose excitation triggers the release of

noradrena-lin from sympathetic nerves at the pancreatic gland

Clonidine is an important therapeutic tool to treat

other pancreatic exocrine disorders (chronic

pan-creatitis, cancer of the pancreas, pancreatic cysts, and

cystic fi brosis of the pancreas) (Lechin, van der Dijs,

Orozco et al 2005d) The abrupt hyposecretory effect

exerted by this drug would explain the relief of acute

pain and the benefi cial chronic therapeutic effects

(Roze, Chariot, Appia et al 1981)

The above reports are good examples that

dem-onstrate the relevance of coupling physiological,

pathophysiological, clinical, and pharmacological

information to outline therapeutic approaches

However, despite this, doctors remain in the same

state and treat pancreatitis throughout stressful and

dramatic harmful procedures

changes All TH-1 autoimmune diseases are caused

by the disinhibition of the thymus gland from the cortisol bridling In addition, the excitatory effect

of the neural sympathetic overactivity at the spleen and sympathetic ganglia contributes to the enhance-ment and further predominance of the TH-1 immu-nological profi le (Fig 5.2) This predominance of the neural sympathetic activity triggers the enhancement

of plasma TH-1 cytokines (γ-interferon, IL-2, IL-12, IL-18, TNF, etc.) On the contrary, enhanced corti-sol level inhibits the thymus gland and increases the plasma values of TH-2 cytokines (IL-4, IL-6, IL-10, β-interferon, and others) whereas adrenaline pro-vokes a cascade of hematological, metabolic, gastro-intestinal, cardiovascular, and respiratory disorders These two types of peripheral endocrine factors (Ad and cortisol) converge to the deviation of the immune system to the TH-2 profi le Overactivity of humoral immunity predominates over cellular immu-nity, in this circumstance (Romagnani 1996; Lechin,

van der Dijs, Lechin 2002a) (Fig 5.3).

Uncoping Stress in the Elderly

Uncoping stress in the elderly differs from that seen in young people Both atrophy of the A6(NA) (Ishida, Shirokawa, Miyaishi et al 2000; Grudzien, Shaw, Weintraub et al 2007) and hyporeactivity of the adrenal gland cause the absolute predominance

of neural over adrenal sympathetic activity observed

in the elderly (Seals, Esler 2000) It is consistent with fi ndings indicating that aging prolongs the stress-induced release of noradrenaline in rat hypo-thalamus (Perego, Vetrugno, De Simoni et al 1993) The assessment of circulating neurotransmitters

in approximately 30,000 subjects carried out in our institute demonstrated that absolute noradrenergic over adrenergic predominance was observed in the elderly In addition, adrenaline plasma level does not increase during exercise; thus the noradrenaline/adrenaline plasma ratio does not show a decrease but an increase (Lechin, van der Dijs, Lechin 1996c) However, signifi cant plasma dopamine rises are always noted in these circumstances Artalejo et al (1985) demonstrated that circulating dopamine is able to inhibit the adrenal glands secretion The aforementioned adrenaline versus noradrenaline and dopamine dissociation, observed during the orthos-tasis and exercise challenge supports the postulation

of the hyperresponsiveness of neural sympathetic activity versus the hyporresponsiveness of the adre-nal sympathetic system seen in the elderly This neu-roautonomic response to the orthostatic and exercise challenge in old subjects when they are submitted

to the aforementioned stressors fi ts well with the orthostatic hypotension but not with the heart rate

cells (Holst, Schaffalitzky, Muckadell et al 1979)

Noradrenergic and serotonergic fi bers end at

intra-pancreatic ganglia whose stimulation abolishes

vagal-induced secretion, by acting at α-2 adrenoceptors

(Alm, Cegrell, Ehinger et al 1967; Holst, Schaffalitzky,

Muckadell et al 1979) These fi ndings are supported

by the capacity of neural sympathetic enhancement

to antagonize the hyperparasympathetic-induced

hypersecretion, which underlies pancreatic cyst

for-mation (Hong, Magee 1970) Considering that

post-ganglionic α-2 receptors mediate sympathetic nerve

effects at this level, we fi nd an explanation for the

benefi ts triggered by clonidine (an α-2 agonist)

in both pancreatic cysts and pancreatitis (Lechin,

Benshimol, van der Dijs et al 1970; Lechin, van der

Dijs, Lechin 2002c; Lechin, van der Dijs, Orozco

2002h) Roze et al (1981) found that a small dose of

intramuscular injected clonidine is able to stop

pan-creatic secretion from the excretory duct abruptly in

experimental rats This peripheral noradrenergic

ver-sus parasympathetic antagonism is consistent with the

inhibitory effects exerted by both A5(NA) and A6(NA)

axons ending at the dorsal motor nucleus of the vagus

located in the medullary area (Barlow, Greenwell,

Harper et al 1971; Lechin, van der Dijs 1989)

In addition, nicotine receptor antagonists

effec-tively block the vagal-induced pancreatic secretion

This fi nding fi ts well with the benefi cial effects that

we obtained by the addition of small doses of

pro-pantheline, a nicotine-antagonist that does not cross

the BBB

Not only ANS but also hormonal

(cholecysto-kinin [CCK]-pancreozymin and secretin)

mecha-nisms are involved in pancreatic exocrine secretion

The release of both hormones is less dependent on

the ANS infl uence (Lechin, van der Dijs, Bentolila

et al 1978; Lechin, van der Dijs 1981e; Lechin

1992b; Lechin, van der Dijs, Orozco 2002b, 2002h)

However, ANS drives are able to interfere with the

secretory hormone release and/or its effects (Lechin,

van der Dijs, Orozco et al 2002h) For instance,

α-adrenergic infl uences are able to interfere with

CCK-pancreozymin effects (Lechin, van der Dijs,

Bentolila et al 1978; Lechin, van der Dijs 1981e;

Lechin 1992b; Lechin, van der Dijs, Orozco 2002b)

Thus, we believe that the therapeutic success we

obtained with this small casuistic of pancreatic cysts

and cystic fi brosis patients has enough scientifi c

sup-port to attempt additional neuropharmacological

approaches to treat these patients

Neuroautonomic and

Immunological Interactions

The levels of both cortisol and adrenaline in the

plasma are responsible for signifi cant immunological

C1 Ad

MR 5-HT

DR 5-HT

A5-NA A6-NA

PVN

V A G A L

Inhibition Excitation

A6-NA = Locus coeruleus DR-5-HT = Dorsal raphe MR-5-HT = Median raphe PVN = Paraventricular nucleus

Figure 5.2 TH-1 autoimmune profi le Predominance

of the A5(NA) neurons is responsible for the inhibition

of both the C1(Ad) (adrenergic) and vagal

(parasym-pathetic) activities In addition, the absence of the

C1(Ad) excitatory drive to the DR(5-HT) neurons is

responsible for the MR(5-HT) predominance At the

peripheral level, raised noradrenaline/adrenaline

plasma ratio is observed The hypoactivity of the

DR(5-HT) and the hyperactivity of the MR(5-HT)

nucleus are responsible for the low plasma tryptophan

as well as the high platelet serotonin levels, always

seen in these circumstances Predominance of neural

sympathetic activity inhibits adrenocortical

secre-tion, which is responsible for the disinhibition of the

thymus gland This latter provokes enhancement of

cell-mediated immunity (TH-1 immunological profi le)

At the blood level, predominance of the cytokines

IL-2, IL-12, IL-18, and γ-interferon is seen in patients

affected by the TH-1 profi le.

Figure 5.3 TH-2 autoimmune profi le This profi le

depends on the release of corticotrophin-releasing

hormone (CRH) from the hypothalamic

paraventricu-lar nucleus (PVN) A positive feedback among the

A6(NA), DR(5-HT), and C1(Ad) is observed at this

cir-cumstance (uncoping stress) Highest adrenaline (Ad)

and cortisol plasma levels are observed during this

disorder Conversely, very low levels of plasma

nor-adrenaline (NA) underlie this profi le Predominance

of corticoadrenal sympathetic activity inhibits the

thymus gland This latter provokes predominance of

humoral immunity (TH-2 immunological profi le) At

the blood level, cytokines IL-6, IL-10, and β-interferon

predominates at this circumstance However, the most

important immunological parameter involved in this

disorder should depend on the natural killer (NK) cell

cytotoxicity against the K-562 target cells This

param-eter is found very low in TH-2 autoimmune patients

Sastry et al (2007) ratifi ed our fi ndings showing that

the raised levels of plasma Ad are responsible for the

inability by NK cells to destroy the K-562 target cells

(Lechin et al 1987).

Inhibition Excitation

A6-NA = Locus coeruleus DR-5-HT = Dorsal raphe MR-5-HT = Median raphe PVN = Paraventricular nucleus

MR 5-HT

DR 5-HT

A5-NA

A6-NA

V A G A L

C1 Ad PVN

Crow et al 2005); thus, any reduction of them would explain the intellectual and psychological distur-bances observed in patients affected by Alzheimer’s disease, whose symptoms resembled those observed

in psychotic patients (Grudzien, Shaw, Weintraub

activ-of l-arginine (50 mg) or digitalis (both of which enhance parasympathetic activity) is enough to sup-press cardiovascular, respiratory, and/or gastrointes-tinal symptoms triggered by any type of stressors in the elderly (Lechin, van der Dijs, Baez et al 2006c).The absolute neural sympathetic predominance observed in the elderly is responsible for all types

of vascular thrombosis seen during aging The absence of the β-adrenergic vasodilator mechanism facilitates all types of vasospasm When the latter phenomenon depends on the effect of circulating noradrenaline at the α-1 receptors located at this level this mechanism would be no more attenuated

by the opposite effect displayed by adrenaline at the vasodilator β-receptors

The A5(NA) predominance over both A6(NA) and C1(Ad) nuclei is responsible for the overwhelm-ing neural sympathetic activity It is similar to that observed in patients with both ED (Kitayama, Naka-mura, Yaga et al 1994) and psychosis, both syndromes caused by auto-aggressive behavior It brings to my

mind the Freud’s sentence: suicide underlies all deaths.

The predominance of noradrenaline over line observed in the peripheral sympathetic system

adrena-in the elderly is also responsible for the TH-1 nological profi le, always observed in the elderly This phenomenon fi ts well with the inhibitory effect exerted by sympathetic nerves on cortisol and adren-aline from the adrenal glands Minimization of the latter redounds in the disinhibition of the thymus This phenomenon is frequently seen despite the fact that this gland tends to involute during senescence However, it has been demonstrated that neural sym-pathetic innervation of the spleen is responsible for

immu-increase seen in them Diastolic, but not systolic, blood

pressure fall is always reported in old subjects during

the 1-minute orthostasis test We found a negative

correlation between the diastolic blood pressure fall

and the rise of dopamine plasma levels (Lechin, van

der Dijs, Lechin 2004c; Lechin, van der Dijs, Lechin

2005a) This phenomenon should be attributed to

the release of dopamine from sympathetic nerves,

which are provided by a dopamine pool This

neuro-transmitter is released before noradrenaline during

sympathetic nerve excitation Dopamine released from

these terminals excites dopamine-2 inhibitory

autore-ceptors located at this level and modulates the further

release of noradrenaline from sympathetic nerves

(Mercuro, Rossetti, Rivano et al 1987; Mannelli,

Pupilli, Fabbri et al 1988) Failure of the modulatory

mechanism contributes to the EH syndrome,

fre-quently seen in the elderly (Lechin, van der Dijs, Baez

et al 2006c) In addition, many research studies

dem-onstrated a negative correlation between CNS-NA

activity and secretion of adrenal glands (Bialik,

Smythe, Sardelis et al 1989) Furthermore, other

fi ndings by Porta et al (1989) demonstrated that

nor-adrenaline overactivity triggers medullar nor-adrenaline

depletion during normoglycemia Other fi ndings

by Sato and Trzebski (1993) demonstrated that the

excitatory response of the adrenal sympathetic nerve

decreases in aged rats This issue has been widely

investigated and discussed by many authors,

includ-ing Seals and Esler (2000) These authors summarize

their research work as follows: (a) tonic whole-body

sympathetic nervous system (SNS) activity increases

with age; (b) skeletal muscle and the gut, but not the

kidney, are some of the most important targets; and

(c) the SNS tone of the heart is highly increased In

contrast to SNS activity, tonic adrenaline secretion

from the adrenal medulla is markedly reduced with

age They also found that the adrenaline release in

response to acute stress is substantially attenuated in

older men

It should be remembered that the pontomedullary

A5(NA) nucleus is responsible for the neural

sympa-thetic activity whereas the medullary C1(Ad) nuclei

are responsible for the adrenal glands secretion

(Fenik, Davies, Kubin 2002) Finally, the CNS nuclei

interchange inhibitory axons, which release

norad-renaline and adnorad-renaline, respectively (Li, Wesselingh,

Blessing et al 1992) Noradrenaline and adrenaline

act at postsynaptic (inhibitory) α-2 receptors located

at both types of neurons

Additional comments should be made with respect

to the progressive reduction of the A6(NA) neurons

with aging (Ishida, Shirokawa, Miyaishi et al 2000;

Grudzien, Shaw, Weintraub et al 2007).It should be

remembered that psychosis is caused by the

congeni-tal defi cit of the A6(NA) neurons (Craven, Priddle,

axons at the DR(5-HT) level, annuls the nance of the DR(5-HT), PVN (CRH), hypophysis (ACTH), and corticoadrenal cascade.

predomi-According to the above there are two different and even opposite types of neuroendocrine circuits which underlie two types of stress profi les: Type 1

is caused by the DR(5-HT,) PVN(CRH), and C1(Ad) predominance, whereas Type 2 depends on the MR(5-HT), CEA, and A5(NA) overactivity At the peripheral level, Type 1 stress would provoke cor-ticoadrenal hypersecretion whereas Type 2 stress would provoke neural sympathetic overactivity and inhibition of the corticoadrenal activity, because sympathetic nerves, which innervate the corticoa-drenal gland (Engeland 1998), inhibit the CRH–ACTH–cortisol cascade

The aforementioned postulation is supported by the assessment of circulating neurotransmitters in approximately 30,000 normal and diseased subjects and a bulk of experimental mammals during the last 36 years (Lechin, van der Dijs, Benaim 1996a;

Lechin, van der Dijs, Lechin 2002a; Lechin, van

der Dijs, Hernandez-Adrian 2006a; Lechin, van der Dijs 2006b)

other than N-methyl d-aspartate (NMDA) receptors

located at these latter (Koga, Ishibashi, Shimada et al 2005) Excitation of the A6(NA) neurons initiates all type of stress Facts showing that MR(5-HT) rather than DR(5-HT) receives heavy glutamate innerva-tion (Tao, Auerbach 2003) contrast with the opposite

fi ndings showing the heavy GABAergic innervation

of the latter but not the former serotonergic nucleus

(Lechin, van der Dijs, Lechin et al 2002a) These

fi ndings allow the understanding why both nergic nuclei are included into two different ana-tomical and physiological circuitries The above anatomical circuitry allows the necessary physiologi-cal independence needed for the accomplishment

seroto-of two distinct behavioral activities Serotonergic axons from these two nuclei inhibit the A6NA) neu-rons The modulatory role exerted by them would depend on the type of stress stimulus This special-ization is possible because DR(5-HT) neurons are excited by the motility behavior whereas MR(5-HT) responds to restraint, photic, acoustic, fear and all types of psychological stimuli (Lechin, van der Dijs, Hernandez-Adrian et al 2006a)

the TH-1 immunological predominance seen in the

elderly (Felten, Felten, Bellinger et al 1988) This

means that the spleen is able to substitute the thymus

immunological activity

PATHOPHYSIOLOGY OF CLINICAL

SYNDROMES

Two Types of Stress Mechanisms

Type 1: Motility Behavior—Acute Stress

Both the A6(NA) and DR(5-HT) neurons receive

excitatory glutamate axons, which trigger the release

of noradrenaline and serotonin, respectively, at

the hypothalamic PVN CRH secreted at this level

excites the ACTH—cortisol cascade and, in addition,

excites the C1(Ad) medullary nuclei Furthermore,

CRH released from axons arising from the PVN

at the A6(NA) and the DR(5-HT) nuclei is

respon-sible for a positive feedback between these two CNS

levels Even more, cortisol released from the adrenal

gland crosses the BBB and excites both the C1(Ad)

and the DR(5-HT) nuclei The latter nucleus, but

not other serotonergic nuclei, is crowded by

excit-atory cortisol receptors In addition, the overexcited

C1(Ad) nuclei send excitatory and inhibitory drives

to the DR(5-HT) and the A5(NA) neurons,

respec-tiv ely Summarizing, the acute stress syndrome

inclu-des overactivity of the A6(NA), DR(5-HT), PVN(CRH),

and C1(Ad) CNS circuitry, and the inhibition of the

A5(NA) nucleus

Type 2: Restraint, Photic, Acoustic, and

Psychological Stimuli—Acute Stress

Predominance of the MR(5-HT) nucleus is

respon-sible for this type of stress MR(5-HT) axons inhibit

both A6(NA) and DR(5-HT) nuclei Both the A6(NA)

and the MR(5-HT) but not the DR(5-HT) neurons

are excited by glutamatergic axons The MR(5-HT)

axons do not innervate the hypothalamic PVN

directly, but throughout polysynaptic drives which

include the CEA, the BNST and the A5(NA) nuclei

and fi nally, the hypothalamic PVN The inhibition

of the A6(NA) by the MR(5-HT) axons triggers the

disinhibition of the A5(NA) neurons, which are also

excited by the CEA + BNST drive The overexcited

A5(NA) nucleus triggers the inhibition of both the

C1(Ad) and the A6(NA) nuclei In addition, the

CRH—ACTH—cortisol cascade is not so intense as

that observed during the Type 1 acute stress, thus the

plasma cortisol rise is not so high to disinhibit the

DR(5-HT) neurons from the MR(5-HT) bridle This

well-known inhibitory effect exerted by MR(5-HT)

always seen in these circumstances Neurochemical investigation carried out at this period demon-strated exhaustion of the DR(5-HT) neurons plus

an excess of extracellular 5-HT at the spinal motor (anterior) horns This latter depends on the release

of serotonin from the disinhibited RP(5-HT) rons, which receive inhibitory DR(5-HT) axons According to the above, this syndrome depends on the predominance of RP(5-HT) over A6(NA) at the anterior spinal horns (Kvetnansky, Bodnar, Shahar

neu-et al 1977; Anisman, Irwin, Sklar 1980; Desan, Silbert, Maier et al 1988; Tanaka, Okamura, Tamada

et al 1994) This syndrome is similar to that observed

in the called akathisia syndrome (restlessness of legs),

usually observed in benzodiazepine’s consumers (Lechin, van der Dijs, Vitelli-Flores et al 1994b; Lechin, van der Dijs, Benaim 1996b); these drugs trigger the inhibition of DR(5-HT) neurons (which are crowded by inhibitory GABA neurons) and dis-inhibition of the RP(5-HT) neurons Summarizing, the exhaustion of both A6(NA) and DR(5-HT) nuclei underlies this disorder However, the fact that the disinhibition of the A5(NA) nucleus from the exhausted A6(NA) axons but not from the overac-tive C1(Ad) nuclei explains the prolongation of the uncoping stress disorder (Granata, Numao, Kumada

et al 1986; Peyron, Luppi, Fort et al 1996; Koob 1999) Nevertheless, the progressive disinhibition of the A5(NA) neurons from the A6(NA) and C1(Ad) nuclei, allows that axons from the former nucleus bridle the RP(5-HT) neurons, whose hyperactivity is responsible for the restlessness syndrome (Hokfelt, Phillipson, Goldstein 1979; Byrum, Guyenet 1987; Zhang 1991; Tanaka, Okamura, Tamada et al 1994; Laaris, Le Poul, Hamon et al 1997; Hermann, Luppi, Peyron et al 1997; Gerin, Privat 1998) This postu-lation is reinforced by fi ndings showing that neuro-pharmacological and/or electrical excitation of the A5(NA) neurons and/or the DR(5-HT) neurons normalized the motility behavior in rats affected

by this syndrome With respect to this, we strated that low doses (10 mg) of amitriptyline or desipramine, intramuscularly injected (which excites A5(NA) neurons), suppresses drastically the restless-ness syndrome (Lechin, van der Dijs, Benaim 1996a) These fi ndings are also consistent with the demon-stration that the A5(NA) neurons send inhibitory axons to the RP(5-HT) neurons (Tanaka, Okamura, Tamada et al 1994)

demon-In humans, the restlessness syndrome is quently seen in benzodiazepine’s consumers and in myasthenia gravis patients (during acute periods) The fact that recovery in this last syndrome is fast with the administration of corticosterone (which excite the DR(5-HT) and/or intramuscularly injec-ted amitriptyline or desipramine, which excites the

fre-The locus coeruleus (LC) or A6(NA) axons

innervate the brain cortex and the pontomedullary

DVC(ACh) and the NTS cholinergic neurons These

two anti-ACh drives provoke the alerting state and

diminish peripheral parasympathetic activity The

augmentation and/or prolongation of this acute

stress phenomenon contributes to the excitation of

the PVN hypothalamic and the C1(Ad) medullary

nuclei, which are responsible for the CRH—ACTH—

cortisol and the adrenal sympathetic cascades,

respectively (Kvetnansky, Bodnar, Shahar et al

1977; Burchfi eld 1979; Liu, Fung, Reddy et al 1991;

Sternberg, Glowa, Smith et al 1992; Calogero, Bagdy,

D’Agata 1998) The fact that CRH is also released at

both the A6(NA) and the DR(5-HT) levels constitutes

a positive feedback mechanism that favors the

pro-longation of the fi ring activity of these nuclei (Koob

1999) Both the A6(NA) and the C1(Ad) axons

over-release noradrenaline and adrenaline, respectively,

at the A5(NA) nucleus Both catecholamines

trig-ger inhibition of the latter, by acting at α-2

inhibi-tory receptors located at the A5(NA) nucleus This

cross talk is responsible for the predominance of the

adrenal sympathetic over the neural sympathetic

observed at the peripheral level during this acute

period (Kvetnansky, Bodnar, Shahar et al 1977;

Burchfi eld 1979) At these circumstances, the

seroto-nin released at the A6(NA) is not enough to be able

for stop the stress cascade because of the

overwhelm-ing release of CRH at the A6(NA) neurons However,

prolongation and/or augmentation of the stressful

process triggers maximal enhancement of the

corti-sol plasma levels This hormone crosses the BBB and

provokes additional excitation of the DR(5-HT)

neu-rons activity because they are crowded by excitatory

cortisol receptors The over-release of serotonin from

the DR(5-HT) axons at the A6(NA) neurons

attenu-ates the stress cascade; however, prolongation of this

process triggers the exhaustion of the DR(5-HT)

neurons The exhaustion and further disappearance

of the activity of the serotonergic nucleus underlies

the uncoping stress phenomenon It is the “learned

helplessness behavior,” “uncontrollable stress,” or

“behavioral despair” (Kant, Mougey, Meyerhoff et al

1989; Szabo, Blier 2001)

Uncoping Stress

Learned helplessness or inescapable

(uncontrolla-ble) stress, also known as behavioral despair

consti-tutes the maximal expression of this syndrome and

is experimentally induced in rats submitted to

pro-longed exercise (e.g., swimming until exhaustion)

These rats do not try more to escape and lie fl at on

the experimental table Hypotonic legs and neck are

opposite physiological profi le (Lechin, van der Dijs, Hernandez-Adrian 2006a) Other fi ndings demon-strate that the A8(DA), A9(DA), and the A10(DA) nuclei display fi ring activities, which parallel the activities of DR(5-HT) and MR(5-HT), respec-tively (Ferre, Artigas 1993; Broderick, Phelix 1997; Jackson, Cunnane 2001; Yan, Zheng, Feng et al 2005) Furthermore, the fact that cortical and subcortical

DA are positively associated with thinking and motility, respectively (Bunney and Aghajanian, 1978) facilitates the understanding of why these two sero-tonergic nuclei are included into the two circuit-ries responsible for the aforementioned profi les, respectively This knowledge allows explaining why mammals interrupt movements to think (Fuxe, Hokfelt, Agnati et al 1977; Herve, Simon, Blanc et al 1981; Herve, Pickel, Joh et al 1987)

Other types of stressors (restraint, photic, sound, and psychological) excite the MR but not the DR serotonergic neurons (Tanaka, Kohno, Nakagawa

et al 1983; Dilts, Boadle-Biber 1995; Laaris, Le Poul, Hamon et al 1997; Midzyanovskaya, Kuznetsova, van Luijtelaar et al 2006; Rabat, Bouyer, George

et al 2006) These fi ndings allow understanding why both stressed mammals and humans present with different clinical, biochemical, and hormonal profi les, according to the distinct types of stressful situations (Lechin, van der Dijs, Hernandez-Adrian 2006a)

The exhaustion of the DR(5-HT) neurons unds in the disinhibition of the subordinate sero-tonergic nuclei: PAG, RM, RO, and RP (Byrum, Guyenet 1987; Krowicki, Hornby 1993; Vertes, Kocsis 1994; Hermann, Luppi, Peyron et al 1997) Thus, serotonin released from the disinhibited nuclei excites all ACh medullary nuclei such as the NTS and the nucleus ambiguus (Behbehani 1982; Newberry, Watkins, Reynolds et al 1992; Porges 1995; Thurston-Stanfi eld, Ranieri, Vallabhapurapu

redo-et al 1999), which interchange modulatory axons with the C1(Ad) medullary nuclei This cross talk

at the medullary level explains the alternancy between the peripheral adrenal sympathetic and parasympathetic activities Maximal oscillations of this binomial circuitry are observed during uncop-ing stress situations Abrupt alternation of adrenal sympathetic and parasympathetic predominance

is observed during these periods (Young, Rosa, Landsberg 1984; Krowicki, Hornby 1993; Porges 1995) Gastrointestinal, biliary, and cardiovascular symptoms would refl ect the hyperactivity of these two opposite ANS profi les The absence of the neu-ral sympathetic activity under these circumstances allows the aforementioned peripheral ANS instabil-ity among the adrenal, sympathetic, and parasympa-thetic activities

A5(NA) neurons, fi ts well with the experimental

fi ndings in rats The failure of oral administration

of both amitriptyline and desipramine to provoke

results similar to that obtained after parenteral

route should be attributed to interference by the liver

uptake of the oral administered drugs This liver

uptake interferes with the fast and direct CNS effect

triggered by the intramuscularly injection We have

successfully treated hundreds of these patients during

acute as well as nonacute episodes with this

neurop-harmacological strategy (Lechin, van der Dijs, Jara

et al 1997b; Lechin, van der Dijs, Pardey-Maldonado

2000; Lechin, van der Dijs, Lechin 2002a)

Other monoaminergic neurons are involved in

the uncoping stress versus coping stress All types of

stressor agents excite the glutamate (pyramidal)

cor-tical neurons Glutamate axons excite the A6(NA) +

MR(5-HT) rather than DR(5-HT) neurons or the

dopaminergic nuclei A10, and A8 + A9 (substantia

nigra) (Olpe, Steinmann, Brugger et al 1989;

Ping, Wu, Liu 1990; Nitz, Siegel 1997; Hervas, Bel,

Fernandez et al 1998; Tao, Auerbach 2003) The

above monoaminergic nuclei are located at the fi rst

or second line of the stress cascade (Calogero, Bagdy,

D’Agata et al 1988; Midzyanovskaya, Kuznetsova, van

Luijtelaar et al 2006) However, other CNS nuclei

receive also glutamatergic axons, such as the A5(NA)

and the C1(Ad) nuclei (Shanks, Zalcman, Zacharko

et al 1991; Fung, Reddy, Zhuo et al 1994; Liu, Fung,

Reddy et al 1995) These glutamate axons do not

arise from cortical but subcortical levels In addition,

both the A6(NA) and the DR(5-HT) nuclei receive

also heavy GABA ergic innervation, which arise

from cortical levels Finally, although the MR(5-HT)

neurons receive both GABA and glutamic cortical

inputs, this latter predominates over the former (Tao,

Auerbach 2003)

Although the A10(DA) mesocortical neurons

receive also glutamate (excitatory) and GABA

(inhibi-tory) axons, these neurons are maximal excited by

the A6(NA) and inhibited by the DR(5-HT) axons

The understanding of this “cross talk” helps to

out-line adequate neuropharmacological therapy for

several psychological and neurological disturbances

(Vezina, Blanc, Glowinski et al 1991; Pozzi, Invernizzi,

Cervo et al 1994; Matsumoto, Togashi, Mori et al

1999; Devoto, Flore, Pani et al 2001; Lechin, van der

Dijs, Lechin et al 2002a; Ishibashi, Shimada, Jang

et al 2005)

The rationality of the aforementioned cross

talk should be understood on the basis of

experi-mental data emanating from a bulk of research

studies For instance, DR(5-HT) neurons fi re

dur-ing movement and cease to fi re durdur-ing

immobil-ity (Trulson, Jacobs 1979; Jacobs, Heym, Trulson

1981) Conversely, MR(5-HT) neurons display the

A6(NA) binomial This excessive response nance) from the A5(NA) and MR(5-HT) may lead

(predomi-to the pathophysiological disorder that underlies the ED Irreversibility of this disorder is responsible for PTSD Hence, the ED syndrome depends on the absolute but reversible predominance of A5(NA) and MR(-5-HT) over the A6(NA) and DR(5-HT) binomial (Lechin, van der Dijs, Orozco et al 1995a, 1995b; Lechin 2006a, 2006b) whereas the PTSD would be the irreversible version of the same disorder

Endogenous Depression

We were the fi rst to demonstrate that ED is caused by hyperneural sympathetic activity (Lechin, van der Dijs 1982; Lechin, van der Dijs, Gómez et al 1983a; Lechin, van der Dijs, Acosta et al 1983b; Lechin, van der Dijs 1984; Lechin, van der Dijs, Jakubowicz

et al 1985a, 1985b; Lechin, van der Dijs, Amat et al 1986; Gomez, Lechin, Jara et al 1988; Lechin, van der Dijs, Vitelli et al 1990a; Lechin, van der Dijs, Lechin et al 1991; Lechin 1992a; Lechin, van der Dijs, Orozco et al 1995a) Additional studies carried out in our and other laboratories demonstrated that

ED is also associated with severe endocrinological disorders

Endogenously depressed patients present with a raised plasma cortisol level in the afternoons, and the level does not show reduction after dexamethasone challenge It should be known that the MR(5-HT) and not the DR(5-HT) is responsible for the 5-HT–CRH–ACTH cascade, which triggers the endocrine disorder in these patients This circuitry does not depend on the DR(5-HT) and PVN hypothalamic nuclei but on the MR(5-HT), CEA, BNST, A5(NA), and anterior hypothalamic area This CNS circuitry

is less accessible to the cortisol and/or sone plasma levels and would thus explain the “non-suppression” of plasma cortisol after dexamethasone challenge, seen in ED patients (Lechin, van der Dijs, Hernandez-Adrian 2006a)

dexametha-Endogenously depressed patients do not show the normal increase in plasma levels of growth hor-mone (GH) when they are challenged with clonidine (an α-2 agonist) This null response is explained by the downregulation of α-2 receptors at the anterior hypothalamic area, which receives heavy innerva-tion from the overexcited A5(NA) axons This abnor-mal response to clonidine, observed in ED patients

is consistent with the postulation that this syndrome

is caused by overactivity of the A5(NA) nucleus and hypoactivity of the A6(NA) neurons (Lechin, van der Dijs, Jakubowicz et al 1985a, 1985b; Eriksson, Dellborg, Soderpalm et al 1986; Lechin, van der Dijs, Jakubowicz 1987a; Lechin, van der Dijs, Vitelli et al

The progressive (chronic) exhaustion of the

A6(NA) and DR(5-HT) binomial observed during

the uncoping stress disorder may lead to the

grad-ual predominance of the A5(NA) and MR(5-HT)

nuclei Both NA and 5-HT axons arising from the

lat-ter inhibit the C1(Ad) and parasympathetic binomial

as well as the medullary serotonergic nuclei (Levine,

Litto, Jacobs 1990; Shanks, Zalcman, Zacharko et al

1991; Laaris, Le Poul, Hamon et al 1997; Koob 1999;

Kvetnansky, Bodnar, Shahar et al 2006) This

emer-gent CNS neurochemical predominance underlies

the “coping stress” syndrome At the peripheral level,

the neural sympathetic overactivity would be

respon-sible for the spastic colon, biliary hypokinesia,

brady-cardia, diastolic blood pressure rise, and many other

physiological changes

The uncoping versus coping stress CNS

mecha-nism and the peripheral mechamecha-nisms that underlie

them are responsible for most, if not all, the

clin-ical syndromes seen during these circumstances,

and will be illustrated with several examples These

examples will include acute pancreatitis, ulcerative

colitis, Crohn’s disease, nervous diarrhea, spastic

colon, biliary dyskinesia, bronchial asthma, EH,

vas-cular thrombosis, hyperinsulinism, duodenal ulcer,

infertility in women, malignant diseases,

thrombocy-topenic purpura, polycythemia vera, cystic fi brosis,

carcinoid tumor, and several autoimmune diseases

In summary, the uncoping stress disorder would

be caused by the exhaustion of the A6(NA) and

A5(NA) nuclei and the absolute predominance of

the C1(Ad) and ACh medullary nuclei Adrenocortical

and adrenal sympathetic predominance over

neu-ral sympathetic activity is observed at the

periph-eral level This adrenocortical hyperactivity is

paralleled by the absolute DR(5-HT) predominance

over MR(5-HT) activity at the CNS Finally, the

absence of the A6(NA) and A5(NA) bridle is

respon-sible for the C1(Ad) and vagal(ACh) nuclei

alternan-cies that underlie the instability of the peripheral

ANS activity, at which level frequent and maximal

adrenal sympathetic versus parasympathetic

oscilla-tions are observed (Lechin, van der Dijs, Jakubowicz

et al 1987a; Lechin, van der Dijs, Lechin et al 1989a,

1993, 1994a; Lechin, van der Dijs, Benaim 1996a;

Lechin, van der Dijs, Lechin 1996c; Lechin, van der

Dijs, Orozco et al 1996d, 1996e; Lechin, van der Dijs,

Lechin et al 1997a; Lechin, van der Dijs,

Hernandez-Adrian 2006a; Lechin, van der Dijs 2006a, 2006b)

Maximal accentuation of the uncoping stress

dis-order leads to the “inescapable” or “uncontrollable”

stress The recovery from this disorder would depend

on the physiological or neuropharmacological

activa-tion of the A6(NA), A5(NA), and MR(5-HT)

activi-ties However, overactivity of the two latter nuclei may

lead to the maximal inhibition of the DR(5-HT) and

The MR(5-HT)-induced prolactin tion is responsible for the mammary and ovarian cysts and infertility, often observed in patients who frequently show an ED profi le With respect to this,

hypersecre-we found that a small dose of daily l-dopa was able

to revert the infertility disorder reported in a bulk

of these patients (Lechin, van der Dijs 1980, 2004a) The fact that l-dopa crosses the BBB and acts at all CNS circuitries is consistent with the earlier postulation

Finally, it should be known that this type of hyperprolactinemia is closely associated to A5(NA) hyperactivity (neural sympathetic hyperactivity) This association allows understanding why TH-1 autoim-mune diseases frequently affect depressed patients

It should be remembered that this autoimmune order depends on the thymus gland disinhibition from the plasma cortisol, which is silenced by the over-release of NA from the sympathetic nerves, at the adrenal gland level Furthermore, it should be known that although ED patients show cortisol levels which are not lowered by the dexamethasone chal-lenge, these patients present with lower-than-normal cortisol values in the mornings because of the under-activity of the DR(5-HT)–CRF–ACTH–cortisol cas-cade at this period This phenomenon refl ects the maximal inhibition of the cortical adrenal gland triggered by the overwhelming neural sympathetic activity, which underlies this syndrome (Robertson, Johnson, Robertson et al 1979; Young, Rosa, Lands-berg 1984; Brown, Fisher 1986; Barbeito, Fernandez, Silveira et al 1986; Porta, Emsenhuber, Felsner

dis-et al 1989)

In Summary, it has been exhaustively strated that the chronic and sustained prolactin plasma rise and the hyperactivity of the neural sym-pathetic (peripheral) branch seen in endogenously depressed subjects depend on the MR(5-HT) pre-dominance over DR(5-HT), which are responsible for the CNS and endocrine disorders observed in this syndrome The mechanisms described might explain the physiological disorders that underlie other syn-dromes such as EH and hyperinsulinism, which should be included into this common pathology.We will go deeply into the experimental, clinical, and therapeutic evidence underlying the pathophysiology

demon-of endogenous (major) depression, which support our point of view dealing with the postulation that a great bulk of the so-called psychosomatic disorders are the other face of the coin of the ED syndrome (Fig 5.4)

Endogenous Depression and Some Psychosomatic Disorders

We demonstrated that major (endogenous) ssed patients presented with neural sympathetic

depre-1990a; Lechin, van der Dijs, Benaim 1996a; Lechin,

van der Dijs, Orozco et al 1996d, 1996e; Lechin, van

der Dijs 2004a)

Raised nocturnal cortisol and prolactin plasma

levels have been the most frequent hormonal fi

nd-ings seen in these patients (Oliveira, Pizarro, Golbert

et al 2000) Most studies associated increase in

pro-lactin levels with an excess of serotonin and a defi cit

of dopamine at the median eminence hypothalamic

nucleus However, the fact that not only l-dopa

(a DA precursor) but also fenfl uramine (a

serotonin-releasing agent) were able to counteract this

hypot-halamic disorder and to reduce the plasma prolactin

level indicates that the CNS disorder underlying the

neuroendocrine disturbance should be explained

It has been shown that enhanced and prolonged

serotonin release at the median eminence depends

on the MR(5-HT) neurons, which display an

over-whelming activity in ED patients, which annuls

DR(5-HT) functioning (Lechin, van der Dijs,

Hernandez-Adrian 2006a) This chronic

hyperprola-ctinemia is respo nsible for the mammary and

ovar-ian cysts and the female infertility presented by

many depressed women, who also show

hyperinsu-linism, obesity, and EH frequently (Lechin, van der

Dijs, Jakubowicz et al 1985a, 1985b; Lechin, van der

Dijs, Hernandez-Adrian 2006a; Lechin, van der Dijs

2006a, 2006b)

A bulk of evidence supports the postulation that

the raised prolactin plasma levels in ED patients

depend on the MR(5-HT) overactivity Although

acute excitation of DR(5-HT) neurons triggers a

peak of plasma prolactin level, only MR(5-HT)

over-activity is responsible for the chronic, sustained rise

in plasma prolactin level seen in ED patients It was

demonstrated that sustained (chronic) raised plasma

levels of this hormone parallels the higher NA

plasma levels, also observed in these patients Indeed,

we were the fi rst to demonstrate that buspirone, a

5-HT-1A agonist, which inhibits the DR(5-HT)

neu-rons, reduced plasma prolactin levels in normal but

not in ED patients (Lechin, van der Dijs, Jara et al

1997c, 1998a) Conversely, we found that this

para-meter is normalized after an adequate

neurophar-macological therapy of ED patients (Lechin, van

der Dijs, Lechin 2002a) This evidence reinforces

the postulation that the hyperprolactinemia in ED

patients would depend on the MR(5-HT), CEA,

A5(NA), BNST, and median eminence circuitry This

circuitry excludes areas which are innervated by the

DR(5-HT) axons

We also demonstrated in 1979 that captivity

(restraint stress) was able to provoke not only the

depressive syndrome but also hyperprolactinemia

and hyperinsulinism in dogs (Lechin, Coll-Garcia,

van der Dijs et al 1979b)

Median raphe

DR 5-HT

A6 (NA)

Median raphe

DR 5-HT

A6 (NA)

A6 (NA)

Median raphe

DR

5-HT BNST

A6 (NA)

Figure 5.4 CNS neurocircuitries underlying pathophysiological mechanisms responsible for the different stress stages and depression Stress: Stressors excite both A6(NA) and DR(5-HT) neurons These effects are triggered by glutamatergic axons Both noradrenaline

and serotonin released from A6 and DR axons excite the hypothalamic paraventricular nucleus (PVN) PVN axons release releasing hormone (CRH) at the median eminence (hypophysis) and the A6(NA) and DR(5-HT) nuclei Thus, CRH is responsible for the hypophysis and adrenal gland excitation, which releases ACTH and cortisol (Crt), respectively In addition, CRH axons excite the medullary Cl(Ad) nuclei that send excitatory (polysynaptic) drives to the adrenal glands, which release adrenaline (Ad) to the blood stream Attenuation of the A6(NA) neurons plus C1(Ad) nuclei is responsible for the disinhibition of the A5(NA) neurons, which receive direct inhibitory axons from the C1(Ad) nuclei The progressive enhancement of the A5(NA) activity redounds in the peripheral neural sympa- thetic overactivity This latter triggers the inhibition of both adrenal and cortical gland secretion.

Considering that both Cl(Ad) axons and plasma cortisol excite DR(5-HT) neurons, the attenuation of both activities redounds in the fading of both excitatory drives to the serotonergic nucleus.

Disappearance of neural sympathetic activity and overwhelming adrenal sympathetic activity underlies the “uncoping stress disorder.” The plasma noradrenaline/adrenaline ratio reaches minimal levels (less than 2; normal, 3 to 5) The highest levels of adrenaline are respon- sible for maximal platelet aggregation, which is responsible for the maximal increase of plasma serotonin (f-5-HT).

Considering that medullary acetylcholinergic (ACh) nuclei, responsible for the peripheral parasympathetic activity, are controlled by both the A6(NA) and A5(NA) nuclei, absolute disinhibition of the former from the two latter nuclei is observed during uncoping stress This phenomenon fi ts well with the lability of the peripheral autonomic nervous system (ANS), which shows frequent oscillations between parasympathetic and adrenal sympathetic periods In addition, uncontrollable parasympathetic drives trigger overexcitation of the enterochromaffi n cells, which release serotonin to the blood stream This indolamine overexcites the medullary area postrema (outside the BBB) This parasympathetic structure is responsible for the maximal enhancement of the medullary (ACh) nuclei It is the physiological disorder named Bezold Jarish syndrome Lowest blood pressure, heart rate, diarrhea, vomits, and so on are seen at this period However, overexcited parasympathetic nuclei are antagonized by the Cl(Ad) medullary nuclei that are responsible for the adrenal glands secretion Thus, parasympathetic and adrenal sympathetic predominance are alternatively observed at peripheral level in mammals, caused by the uncoping stress disorder Findings showing that adequate excitation of the pontine NA and 5-HT nuclei is able to normalize this disorder demonstrate that the absolute failure of these nuclei is responsible for the uncontrollable stress syndrome.

Endogenous depression: Exhaustive evidence demonstrated that this syndrome is caused by the absolute predominance of the

periph-eral neural sympathetic over adrenal sympathetic activity This periphperiph-eral disorder depends on the predominance of the A5(NA) over the Cl(Ad) nucleus In addition, considering that the A5(NA) and the A6(NA) interchange direct inhibitory axons, predominance of the former results in the inhibition of the latter.

Several mechanisms explain the overwhelming predominance of MR(5-HT) over DR(5-HT) that underlies this syndrome, namely, the exhaustion of the Cl(Ad) and DR(5-HT) axis, as demonstrated by the lower-than-normal levels of both adrenaline and cortisol plasma levels

in mammals affected by this syndrome.

1994c; Lechin 1992b; Lechin, van der Dijs, Orozco

et al 1995b; Lechin, van der Dijs, Benaim 1996a; Lechin, van der Dijs, Orozco 2002b; Lechin, van der Dijs, Lechin 2002c)

Our research work allowed us to conclude that both biliary dyskinesia and the irritable bowel syndrome (IBS) should be considered as somatization syndromes (depending on ED) rather than true gastrointestinal diseases In addition, we have exhaustively demon-strated that ED is closely associated to TH-1 autoim-mune disorders This hypothesis is reinforced by our

fi ndings showing that the therapeutic effects triggered

by an adequate neuropharmacological therapy was able to suppress not only gastrointestinal and psychi-atric symptoms but also the immunological disorders (Lechin, van der Dijs, Lechin et al 1989a; Lechin, van der Dijs, Vitelli et al 1990a; Lechin 1992a; Lechin, van der Dijs, Hernandez-Adrian 2006a; Lechin 2006b; Lechin, van der Dijs 2007a, 2007b)

The fi ndings showing no reduction of the els of plasma cortisol after the dexamethasone challenge may be explained because this neuro-endocrine disorder depends on the MR(5-HT) overactivity This statement is supported by facts showing that whereas the DR(5-HT)–PVN(CRH)–ACTH–cortisol circuitry overactivity observed during acute stress is inhibited (suppressed) by dexameth-asone, the disorder responsible for the nocturnal (not diurnal) hypersecretion of cortisol, observed

lev-in ED patients, would depend on another circuitry

We have quoted enough evidence showing that MR(5-HT)–CEA–BNST–PVN circuitry is less acces-sible to the circulating dexamethasone Even more, the demonstrated fact that the DR(5-HT) but not MR(5-HT) neurons are crowded by both CRH and cortisol (excitatory) receptors (Kalin, Weiler, Shelton 1982; Laaris, Le Poul, Hamon et al 1997; Gerendai, Halasz 2000; Vazquez, Bailey, Dent et al 2006)

fi ts well with our postulation The above fi ndings afford defi nitive explanations to the controversial facts showing that acute stress is caused by elevated cortisol plasma levels in the morning whereas ED patients show this endocrine disorder at night (Roy 1988; Yehuda, Teicher, Trestman et al 1996; Choi, Furay, Evanson et al 2007), at which period the DR(5-HT) but not the MR(5-HT) neurons show signifi cant fading (Lechin, van der Dijs, Lechin et al 2002a; Lechin, Pardey-Maldonado, van der Dijs et al 2004a; Lechin, van der Dijs, Lechin 2004b)

The aforementioned CNS circuitry disorder, which underlies ED, might also explain the lack of increase

in plasma levels of growth hormone when ED patients were challenged with a dose of oral clonidine (Lechin, van der Dijs, Jakubowicz et al 1985a, 1985b; Lechin, van der Dijs 2004a)

hyperactivity (higher than normal NA plasma levels),

which was also underlying distal colon hypertonicity

(spastic colon) (Lechin, van der Dijs 1982) Both

psy-chiatric and gastrointestinal disorders were improved

with the administration of some

neuropharmaco-logical agents that were able to deplete CNS

seroto-nin stores (Lechin, van der Dijs, Gómez et al 1982a,

1983a; Lechin, van der Dijs, Acosta et al 1983b) These

fi ndings were further ratifi ed and amplifi ed in other

research studies (Lechin, van der Dijs, Jakubowicz

et al 1985a, 1985b) These studies allowed us to

pos-tulate that the CNS circuitry underlying the

endog-enous depressive syndrome includes hyperactivity of

both the MR(5-HT) and the A5(NA) nuclei and

hypo-activity of the C1(Ad) medullary nuclei In addition,

we found that endogenously depressed patients also

showed raised levels of plasma cortisol at night but not

in the mornings Furthermore, we also demonstrated

that endogenously depressed patients had high levels

of both plasma noradrenaline and p5-HT, and low

levels of plasma adrenaline Both neurochemical and

endocrine disorders were associated to adrenal gland

hypoactivity and neural sympathetic hyperactivity

Finally, we afforded evidence that allowed the

associa-tion of the low levels of plasma tryptophan detected in

ED patients to hypoactivity of the DR(5-HT) nucleus

These fi ndings have received additional support

from the routine peripheral neuroautonomic

assess-ment of these patients as well as the therapeutic

suc-cess obtained in hundreds of them The fact that our

neuropharmacological therapy normalized not only

clinical but also neurochemical, endocrinological ,

andneuroautonomic disorders gave a defi nitive

sup-port to our postulation (Lechin, van der Dijs, Gómez

et al 1983a; Lechin, van der Dijs, Acosta et al 1983b;

Lechin, van der Dijs, Jakubowicz et al 1985b; Lechin,

van der Dijs, Orozco et al 1995a; Lechin, van der

Dijs, Benaim 1996a; Lechin, van der Dijs,

Hernandez-Adrian 2006a; Lechin, van der Dijs 2006a, 2006b)

Other research studies carried out in our

insti-tute demonstrated that not only gastrointestinal but

also biliary motility disorders should be associated

with ED For instance, patients affected by the

spas-tic colon syndrome (hyperactivity of the rectosigmoid

function) (Chowdhury, Dinoso, Lorber 1976) also

presented with biliary motility disorders such as

bili-ary dyskinesia and no gallbladder emptying after the

test meal (Lechin, van der Dijs, Bentolila et al 1977a,

1977b, 1978; Lechin, van der Dijs 1979a, 1979b, 1979c,

1981a, 1982; Lechin, van der Dijs, Gómez et al 1982a,

1982b, 1982c, 1983a; Lechin, van der Dijs, Acosta et al

1983b; Lechin, van der Dijs, Jakubowicz et al 1985a,

1985b; Lechin A, Jara, Rada et al 1988; Lechin M,

Jara, Rada et al 1988a; Lechin, van der Dijs, Gómez

et al 1988b; Lechin, van der Dijs, Lechin-Báez et al

respectively This postulation has received additional support from a great deal of other research studies carried out in our institute The above fi ndings led

us to postulate that the ED syndrome is caused by a CNS circuitry that includes the predominance of the A5(NA) over A6(NA) + C1(Ad) nuclei as well as the MR(5-HT) over DR(5-HT) predominance (Lechin, van der Dijs, Hernandez-Adrian et al 2006a) Conversely, the uncoping stress syndrome would be caused by the opposite profi le: C1(Ad) and DR(5-HT) predominance over A5(NA) and MR(5-HT) (Lechin, van der Dijs, Lechin et al 1992a)

Akathisia Syndrome (Restlessness)This syndrome is frequently observed in chronic benzodiazepine’s consumers (Lechin, van der Dijs, Vitelli-Flores et al 1994b, Lechin, van der Dijs, Benaim 1996b) The well-known fact that benzodiazepines inhibit the DR(5-HT) and the A6(NA) but not the MR(5-HT) neurons would explain the pathophysio-logical disinhibition of the RP(5-HT) neurons respon-sible for this syndrome Doctors prescribe l-dopa to these patients order to ameliorate symptoms affecting them The improvement triggered by this dopamine precursor depends on the fact that not only NA axons but also DA axons innervate the anterior spinal horns Both catecholamines cooperate to the enhancement

of the motility behavior and the muscular tone These

DA axons arise from DA neurons (A11 nucleus) located

at the hypothalamic level In addition, it should be remembered that the anterior (motor) spinal horns also receive excitatory glutamic and inhibitory GABA axons The latter predominate in those patients who consume GABA mimetic drugs such as benzodiaz-epines (Hokfelt, Phillipson, Goldstein 1979)

In summary, it is possible to understand that the inescapable or uncontrollable stress syndrome depends on the exhaustion of the A6(NA), A5(NA), and the DR(5-HT) neurons and the disinhibition of the subordinated Ad(C1) and 5-HT(RP) nuclei This postulation receives additional support from fi ndings which demonstrated that not only DR(5-HT) but also A5(NA) axons inhibit RP(5-HT) neurons (Speciale, Crowley, O’Donohue et al 1978; Li, Wesselingh, Blessing 1992; Tanaka, Okamura, Tamada et al 1994), which release serotonin at the anterior spinal horns (Zhang 1991) The opposite profi le showing the recovery and predominance of the A5(NA) and the MR(5-HT) neurons would shift the uncoping stress

to a coping stress profi le However, prolongation of the latter would lead to the ED profi le [A5(NA) and MR(5-HT) predominance] Furthermore, the fact that the A5(NA) interchanges inhibitory axons with the C1(Ad) medullary nuclei would explain the abso-lute inhibition of the adrenal sympathetic activity that

Endogenous Depression and Hyperinsulinism

In 1979, we demonstrated that the depressive

syn-drome induced by captivity (restraint stress) in

exper-imental dogs was caused by the increase of both

noradrenaline and p5-HT in the blood (Lechin,

Coll-Garcia, van der Dijs et al 1979b) In addition,

we also demonstrated that these dogs showed a rise

of both insulin and glucose (insulin resistance)

Furthermore, in 1991 we also published a research

article, which demonstrated that ED patients showed

hyperinsulinism but not hypoglycemia (Lechin, van

der Dijs, Lechin et al 1991) These patients also had

higher than normal levels of noradrenaline, which

were increased after the oral glucose load (3 hours)

On the contrary, plasma adrenaline levels did not rise

throughout the postprandial period in these patients

Thus, the noradrenaline/adrenaline plasma ratio

augmented throughout the test This

neurotransmit-ters profi le was paralleled by both diastolic blood

pressure and plasma insulin rises Conversely, systolic

blood pressure and heart rate remained constant or

showed slight decreases throughout the test The fi

nd-ing that the therapy with doxepin (50 mg before bed)

normalized clinical, neuroautonomic, metabolic, and

cardiovascular parameters (within the 4 weeks of

treatment), allowed us to postulate that an A5(NA)

predominance over C1(Ad) was responsible for the

peripheral disorder (neural sympathetic over adrenal

sympathetic predominance) Eighty-three percent of

these patients showed a depressive profi le when they

were tested with the Hamilton Depression Rating

Scale

Other patients affected by postprandial

hypogly-cemia and hyperinsulinism (included in this research

study) showed the opposite clinical, metabolic, and

neuroendocrine profi les Namely, they presented

with abrupt hypoglycemia 45 to 50 minutes after the

oral glucose load, which was followed by adrenaline

peaks (10 to 15 minutes later) Dramatic heart rate

and systolic blood pressure but not diastolic blood

pressure increases paralleled adrenaline peaks This

group of patients also improved with the doxepin

therapy However, the fact that the former but not

the latter group showed both cortisol and growth

hormone resistance to the dexamethasone and

cloni-dine challenges, respectively, allowed us to postulate

that ED was responsible for the postprandial

hypo-glycemia observed in them On the contrary, taking

into account that the second group did not show a

depressive profi le, when tested with the Hamilton

Depression Rating scale, allowed us to assign them

the uncoping stress label Summarizing these results

and many others sprouted from the neuroendocrine

and neuroautonomic investigation, we concluded that

neural sympathetic and adrenal sympathetic

hyperac-tivities underlie ED and uncoping stress syndromes,

Yohimbine (5 mg) or regitine orally, (before both

2

breakfast and lunch) Both are α-2 antagonists that trigger the release of NA from the exhausted A6(NA), but not from the overactive A5(NA) neu-rons In addition, these α-2 antagonists will excite the underactive C1(Ad) neurons that are able

to antagonize the A5(NA) neurons (both nuclei interchange inhibitory axons) (Fenik, Marchenko, Janssen et al 2002) The α-2 antagonists also excite DR(5-HT) neurons, which are crowded by α-2 pre-synaptic inhibitory autoreceptors (Raiteri 2001).Amitriptyline or desipramine (10 mg) injected (at

3

morning) intramuscularly Both drugs are taken up and metabolized in the liver after oral administra-tion Thus, the parenteral administration enables these drugs to avoid the obstacle, cross the BBB, and directly excite the hypoactive A6(NA) but not the hyperactive (A5)NA neurons Considering that amitriptyline is an inhibitor of not only noradren-aline uptake but also 5-HT uptake, it would addi-tionally potentiate the underactive DR(5-HT) but not the hyperactive MR(5-HT) neurons

Sibutramine (10 mg before breakfast), only if

nec-4

essary This drug inhibits the noradrenaline uptake and is, in addition, able to trigger noradrenaline and dopamine releases (amphetamine-like effects).Tianeptine 3 mg (before breakfast and lunch)

5

This serotonin uptake–enhancing agent inhibits the release of serotonin from the MR(5-HT) axons These neurons display overwhelming fi ring activity

noradrena-or both of them underlies the shnoradrena-ort-REM latency seen in exhausted and in depressed patients In addition, this neuropharmacological strategy would interfere with the precocious nocturnal fading of the above nuclei

Mirtazapine (30 mg) before bed This drug is a

7

noradrenaline (α-2) as well as 5-HT-2 antagonist, which triggers the release of both types of neu-rotransmitters from the disinhibited A6(NA) and DR(5-HT) axons, respectively These excitatory effects provoked by mirtazapine are further poten-tiated by the previous administration of doxepin or imipramine These latter drugs interfere with both noradrenaline and serotonin uptake This pharma-cological manipulation favors the normalization of the sleep cycle because it prolongs the SWS dura-tion and avoids the short-REM sleep latency

Absolute disappearance of psychiatric, cal, neuroendocrine, and immunological disorders is

neurologi-has always been found in thousands of ED patients

investigated (Li, Wesselingh, Blessing et al 1992;

Fenik, Marchenko, Janssen et al 2002)

Endogenous Depression and

Essential Hypertension

We demonstrated in 1993 that the EH patients but

not the non–essential hypertensive patients showed

the hyperinsulinism (insulin resistance) syndrome

(Lechin, van der Dijs, Lechin et al 1993)

Further-more, we also reported that these patients fulfi lled

the diagnostic criteria for depression when they were

tested with the Hamilton Depression Rating Scale

These clinical research fi ndings allowed us to

postu-late that both the EH and the depression syndromes

are caused by similar CNS disorders

Both syndromes showed enhanced neural

sym-pathetic activity In addition, essential hypertensive

patients frequently present with the ED clinical

pro-fi le Both of them also showed diastolic blood

pres-sure increase at the 1-minute orthostasis challenge

(Lechin, van der Dijs, Lechin et al 1997a) Finally,

mammary and ovarian cysts, infertility, rheumatoid

arthritis, scleroderma, multiple sclerosis, and other

TH-1 autoimmune diseases are frequently associated

with both ED and EH (Lechin, van der Dijs, Orozco

et al 1995a, 1996e; Elenkov, Wilder, Chrousos et al

2000; Koutantji, Harrold, Lane et al 2003; Lechin,

van der Dijs 2004a; Lechin, van der Dijs, Lechin

2004c, 2005a; Beretta, Astori, Ferrario et al 2006;

Wallin, Wilken, Turner et al 2006; Isik, Koca, Ozturk

et al 2007) Special attention should be devoted to

our fi ndings showing that both ED and EH patients

are affected by the hyperinsulinism syndrome This

issue has been widely commented on in two recently

published review articles (Lechin, van der Dijs 2006a,

2006b)

The fact that all these patients are signifi cantly

improved by a common neuropharmacological

ther-apeutic approach to revert the neural predominance

over adrenal sympatheticactivity reinforces our point

of view Special mention should be made with respect

to multiple sclerosis patients who have been

abso-lutely cured by this therapy (unpublished results)

Our therapeutic strategy is addressed at

revert-ing the predominance of A5(NA) over A6(NA)

and C1(Ad) and that of MR(5-HT) over DR(5-HT)

Summarizing this issue, we prescribed the following

drug therapies:

Noradrenaline uptake inhibitor (such as

desipra-1

mine 25 mg; or maprotyline 75 mg; or reboxetine

30 mg) before both breakfast and lunch (but not

before supper) These drugs would excite the

inhibited A6(NA) rather than the overactive A5(NA)

neurons

before bed This drug is an α-2 and 5-HT-2 nist, which favors the release of both noradrenaline and serotonin from their axons A small dose of 5-hydroxytryptophan (a serotonin precursor) would

antago-be added antago-before antago-bed (25 to 50 mg) In addition to all these drugs, we also prescribed 3 mg of tianept-ine (a 5-HT uptake enhancer) both before breakfast and lunch Yohimbine is able to excite both A6(NA) and DR(5-HT) neurons but not MR(5-HT) neurons, which are not crowded by α-2 inhibitory receptors

Psychotic Syndrome

We demonstrated in 1980 that noradrenaline nist drugs such as dihydroergotamine, phentolamine, and clonidine but not dopamine-blocking agents inhibit the distal colon hypermotility (phasic waves) always present in psychotic patients during relapses (Lechin, van der Dijs 1979c; Lechin, Gómez, van der Dijs et al 1980a; Lechin, van der Dijs, Gómez et al 1980b) This distal colon motility profi le strongly suggested that both the acute clinical and physiolog-ical disorders were triggered by CNS noradrenergic overactivity Hence, we postulated that an excess of CNS noradrenaline and not dopamine was respon-sible for the acute psychotic episodes (Lechin, van der Dijs, Gómez et al 1980b; Lechin, van der Dijs 1981b, 1981c)

antago-The fact that clonidine, an α-2 agonist that reduces CNS A5(NA) activity, but not DA antagonists, was able

to suppress both gastrointestinal and acute psychotic episodes allowed us to postulate that both gastrointes-tinal and psychiatric symptoms in psychotic subjects would depend on CNS noradrenaline overactivity Then, we stated that an excess of CNS noradrenaline and not dopamine underlies the psychotic syndrome (Lechin, van der Dijs 1979c, 1979d; Lechin, Gómez, van der Dijs et al 1980a; Lechin, van der Dijs 1981b, 1981c, 1982; Lechin, van der Dijs, Gómez et al 1983c; Lechin, van der Dijs 2005a)

These fi ndings allowed us to successfully treat hundreds of psychotic patients during acute epi-sodes, with clonidine, a drug that bridles hyperac-tive CNS-NA and/or CNS-Ad nuclei, but not CNS-DA nuclei The fact that the peripheral physiological (gastrointestinal) parameters as well as the abnormal levels of circulating neurotransmitters showed differ-ent profi les during acute and nonacute periods led us

to go deeply into both the clinical and ical abnormal phenomena underlying the psychotic syndrome at these two periods.We demonstrated that whereas high phasic activity (waves) and low sigmoi-dal tone (lowered baseline) were observed during the acute periods, the opposite profi le was observed during nonacute (depressive) periods: low phasic activity and high sigmoidal tone In addition, the

neurochem-observed within the fi rst 8 to 16 weeks, after which

slow and progressive reduction of the doses of the

drugs should be attempted In our long experience

with this issue, we have had no failures with this

ther-apeutic approach We have maintained this treatment

during several months, if necessary Higher doses

are not required Interruptions of this therapy would

depend on the clinical assessment We never

admi-nister cortisol or dexamethasone and/or prednisone

to our patients

Post-traumatic Stress Disorder

PTSD is caused by the absolute and irreversible

exhaustion of the A6(NA) and DR(5-HT) This CNS

circuitry disorder is similar to that seen in psychotics

We have had the opportunity to investigated six

subjects affected by this syndrome All of them were

diagnosed by more than one psychiatrist and all them

satisfi ed the clinical criteria necessary to be labeled

with this diagnosis

The neurochemical assessment carried out in

these patients revealed very high levels of plasma

noradrenaline and p5-HT and low levels of plasma

adrenaline, dopamine, and f5-HT In addition, very

low levels of plasma tryptophan were also detected

In accordance with our long experience with this

type of assessment, these patients showed the same

plasma neurotransmitters profi le that underlies the

psychotic syndrome This syndrome depends on

the A6(NA) and DR(5-HT) maximal hypoactivity

and A5(NA) and MR(5-HT) hyperactivity Owing

to the fact that the A10-DA mesocortical neurons

depend on the excitatory A6(NA) axons, both

dopa-mine and noradrenaline defi cits should be found at

the frontal cortex level in both PTSD and psychotic

patients

The aforementioned fi ndings reinforce our

hypothesis that PTSD depends on an irreversible

def-icit of A6(NA) neurons, which would be accentuated

after the sudden death of these neurons, which occurs

during uncontrollable stress episodes Defi nitive and

irreversible A5(NA) and MR(5-HT) predominance

would result in these circumstances

We prescribed to the PTSD patients the same

neuropharmacological therapy that is advised for

psychotic patients This therapy includes drugs that

excite the A6(NA) neurons (intramuscularly injected

amitriptyline (10 mg) and prostigmine (15 mg), and

oral olanzapine (5 mg), yohimbine (2.5 mg),

desipra-mine (25 mg), or any other noradrenaline-uptake

inhibitor (maprotyline, reboxethine, etc) These drugs

must be administered before breakfast In addition,

we prescribed doxepin or imipramine (25 mg) or any

other noradrenaline and serotonin uptake inhibitor

before supper Finally, we added mirtazapine (30 mg)

not only during supine-resting state but also after different types of challenges, allowed us to conclude that whereas the p5-HT level is positively correlated with the activity of the MR(5-HT) neurons, a negative correlation exists between plasma tryptophan and DR(5-HT) activity We discussed this issue in a review article (Lechin, van der Dijs, Hernandez-Adrian 2006a) where we quoted a great deal of data sup-porting this postulation Thus, the very low levels of plasma tryptophan that we always found in psychotic patients during acute periods should be associated to the predominance of MR over DR.

Summarizing, the great bulk of data lated by our research group dealing with the neuro-chemical, neuroautonomic, and neurophysiological assessment of hundreds of psychotic patients during both acute and nonacute periods led us to postulate that this syndrome is caused, at the CNS level, by an A5(NA) and MR(5-HT) predominance over A6(NA) and DR(5-HT) In addition, a defi cit of the A10(DA) activity (dopamine mesocortical neurons) should par-allel the A6(NA) defi cit (Knable, Hyde, Murray et al 1996; Craven, Priddle, Crow et al 2005) This well-demonstrated fact fi ts well with others showing that A6(NA) axons innervate A10(DA) neurons, which are crowded by α-1 excitatory receptors (Tassin 1992) Thus, any A6(NA) defi cit should redound in the DA underactivity at the cortical level Patients with other syndromes (hyperactive, PTSD, and Alzheimer’s dis-ease) also share this disorder

accumu-ED patients (during relapsing periods) should also be included among the CNS (neurochemical and neuroautonomic) psychotic profi le disorder This postulation is consistent with our neurochemical research studies, which demonstrated that they pre-sent with maximal raised levels of both plasma nor-adrenaline and p5-HT levels and very low levels of plasma tryptophan at these periods In our long expe-rience with this issue, we found a positive correlation between the neurochemical disorders and the suicide attempts, which should be considered as a psychotic symptom

Psychotic DisorderSummarizing, psychotic syndrome is caused by ana-tomical and physiological defi cits of the A6(NA), A10(DA), and DR(5-HT) nuclei Hence, noradrena-line, dopamine, and serotonin are under-released at the frontocortical brain areas These defi cits would result in the predominance of the subcortical nuclei: A5(NA),MR(5-HT), A8(DA), and A9(DA)

The A5(NA) and MR(5-HT) binomial would dominate over the A6(NA) and DR(5-HT) during acute psychotic periods, whereas the MR(5-HT) and medullary parasympathetic activities would predomi-nate during psychotic depressive periods

pre-circulating neurotransmitters profi le showed raised

noradrenaline/adrenaline ratio and normal or low

p5-HT during acute psychotic periods and lowered

noradrenaline/adrenaline ratio and highest p5-HT

values during nonacute (depressive) periods This

lat-ter neurotransmitlat-ter profi le is also seen in psychotic

patients taking antipsychotic drugs The fi ndings that

these patients also showed sedation and other clinical

symptoms of hyperparasympathetic predominance

after the clonidine administration allowed us to think

that ACh and serotonergic overactivity was

responsi-ble for the clinical profi le observed during nonacute

psychotic (depressive) periods

Neuroautonomic and neurophysiologic data have

demonstrated that the A5(NA) and the MR(5-HT)

are included into a common CNS circuitry, which is

shared by the CEA and the BNST This circuitry

dis-plays antagonistic activity to other circuitry integrated

by the A6(NA), DR(5-HT), and the hypothalamic

PVN nuclei (Lechin, van der Dijs, Hernandez-Adrian

2006a)

Considering that the A6(NA) is underdeveloped

in psychotic subjects (Craven, Priddle, Crow et al

2005), it cannot exert the normal modulatory role,

which depends on the bridling of the A5(NA)

neu-rons by A6(NA) axons (Cedarbaum, Aghajanian

1978; Byrum, Guyenet 1987; Ennis, Aston-Jones

1988) Conversely, the latter nucleus should inhibit

the former in psychotic patients Furthermore,

tak-ing into account that MR(5-HT) axons bridle both

the A6(NA) and the DR(5-HT) neurons, the A5(NA)

and MR(5-HT) binomial activity should overwhelm

the A6(NA) + DR(5-HT) nuclei (Lechin, van der

Dijs, Hernandez-Adrian 2006a) In addition, fi

nd-ings showing that the A5(NA) nucleus interchanges

inhibitory axons with the medullary parasympathetic

nuclei (Iwasaki, Kani, Maeda 1999; Fenik, Marchenko,

Janssen et al 2002) and furthermore, sends inhibitory

axons to the C1(Ad) medullary nuclei (Li, Wesselingh,

Blessing 1992) fi t well with the understanding of the

pathophysiological mechanisms that underlie the two

clinical alternating periods seen in psychotic patients

(maniac and depressive) At the peripheral level, both

neural sympathetic and parasympathetic

predomi-nance would be observed, during manic and

depres-sive periods, respectively Increased phasic activity

and low sigmoidal tone versus none or low phasic

activity and high sigmoidal tone will be observed

dur-ing acute and nonacute psychotic (depressive) clinical

syndromes, respectively (Lechin, Gómez, van der Dijs

et al 1980a; Lechin, van der Dijs, Gómez et al 1980b,

1982a)

The DR(5-HT) and the MR(5-HT) nuclei are

involved into the CNS circuitry disorder that

under-lies the psychotic syndrome to a great extent The

assessment of circulating neurotransmitters in

approximately 30,000 normal and diseased subjects,

It has been exhaustively demonstrated that these abnormal fi ndings support the postulation that the predominance is closely associated to the aggressive behavior, which is always present in all patients with the aforementioned psychiatric syndromes.

Our long experience dealing with the cal plus neuroautonomic assessment of all types of psy-chiatric and/or somatic diseases allow us to postulate that the aforementioned patients share some common CNS circuitry disorders This common profi le would

neurochemi-be integrated by a defi cit of the A6(NA), A10(DA), + and DR(5-HT) neurons, all of which innervate the frontal cortical area The neurochemical defi cit at cortical level would favor the predominance of the A5(NA), A8(DA), A9(DA), and MR(5-HT) subcorti-cal CNS circuitry Indeed, this CNS profi le underlies the psychotic syndrome schizophrenia Our research group has investigated this issue since 1981, when

we published our fi rst reports dealing with the drenergic hypothesis of the schizophrenia (Lechin, van der Dijs 1981c) These preliminary studies have been further ratifi ed by us and many other research-ers (Yamamoto, Hornykiewicz 2004; Lechin, van der Dijs 2005a) In addition, we have had the opportunity

nora-to outline successfully neuropharmacological apy for a bulk of these patients

ther-Our neuropharmacological therapeutic approach

is aimed at the enhancement of the A6(NA) and A10(DA) activity, to restore the predominance of this binomial over the A5(NA), A8(DA), and A9(DA) (Vezina, Blanc, Glowinski et al 1991; King, Zigmond, Finlay 1997) This target is reached by the administration of

a noradrenaline-uptake inhibitor (such as desipramine

or maprotyline or reboxethine), a releasing agent (such as yohimbine or regitine or idaxozan), a noradrenaline precursor (phenylalanine or l-tyrosine), olanzapine, which excites A6(NA) neurons (Dawe, Huff, Vandergriff et al 2001), and an MAO-B inhibitor (such as selegiline) The rationality of this treatment depends on fi ndings showing that the two former drugs would act at the underactive A6(NA) and not at the hyperactive A5(NA) nucleus Considering that A6(NA) axons excite A10(DA) mesocortical neu-rons, selegiline should interfere with the MAO-B enzyme, which catabolizes dopamine at this level Finally, we add a small dose of modafi nil or adrafi nil after breakfast This α-1 agonist is able to excite recep-tors located at the A10(DA) mesocortical neurons (Tassin 1992), which release dopamine from DA axons

noradrenaline-It should be remembered that dopamine released at cortical levels is not taken up by DA axons (as occurs

at subcortical areas) This neurotransmitter is destroyed

by the MAO-B enzyme; thus, inhibition of this enzyme would interfere with the disappearance of dopamine at this level (Vezina, Blanc, Glowinski et al 1991)

In addition, we prescribe an adequate pharmacological therapy addressed to normalize

neuro-Similar Common Disorders Shared

by Endogenous Depression, Psychotic,

Attention-Defi cit Hyperactive Disorder,

Post-traumatic Stress Disorder, and

Alzheimer’s Patients

We do not pretend to afford a long and detailed list

of specifi c symptoms with reference to each of these

syndromes; however, it is well known that all patients

with these disorders show a low intellectual

capabil-ity, defi cit of memory, attention, and affection as well

as learning disability In addition, they also show an

aggressive behavior and a low prepulse inhibition

(Lechin, van der Dijs, Lechin 1979a; Lechin, van der

Dijs 1989; Lechin, van der Dijs, Lechin 2002a) In

addition, all of them present with a neurochemical

profi le characterized by raised levels of circulating

noradrenaline and p5-HT Conversely, both

adren-aline and plasma tryptophan levels are found to be

lower than normal in all of them (Lechin, van der

Dijs, Orozco et al 1995a) This neurochemical profi le

worsens during orthostasis and exercise challenges

Diastolic blood pressure, but neither systolic blood

pressure nor heart rate, showed normal increases in

healthy subjects This phenomenon is consistent with

the postulation of the predominance of the

periph-eral neural sympathetic activity over the adrenal

sym-pathetic activity At the CNS level, predominance of

the A5(NA) over the C1(Ad) pontomedullary nucleus

would be responsible for the peripheral sympathetic

disorder (Lechin, van der Dijs 2006a) These fi ndings

receive support from those of many others

research-ers (Rotman, Zemishlany, Munitz et al 1982; Kalin,

Weiler, Shelton 1982; Rogeness, Mitchell, Custer et al

1985; Roy, Pickar, Linnoila et al 1985; Banki, Bissette,

Arato et al 1987; Faludi, Magyar, Tekes et al 1988;

Leake, Griffi ths, Ferrier 1989; Murburg, McFall, Lewis

et al 1995; Yehuda, Teicher, Trestman et al 1996; Roy

1999; Seals, Esler 2000)

Several neuroendocrinological disorders are also

common to all the aforementioned psychiatric

syn-dromes These include lower-than-normal cortisol

response to the dexamethasone challenge as well as

lower-than-normal growth hormone response to the

clonidine challenge In addition, this α-2 agonist does

not provoke the normal plasma noradrenaline level

reduction when these patients are challenged with

this drug Other common neuroendocrinological

dis-order shared by all these patients is the chronically

elevated prolactin plasma level (Lechin, van der Dijs,

Jakubowicz et al 1985a, 1985b; Lechin 1992c)

Increased p5-HT and reduced plasma tryptophan

levels are always observed in these patients A bulk of

evidence supports the postulation that these abnormal

fi ndings should be associated with the absolute

predom-inance of the MR(5-HT) activity over the DR(5-HT)

activity (Lechin, van der Dijs, Hernandez-Adrian 2006a)

IL-12, IL-18, γ-interferon) (Madden, Felten, Felten

et al 1989; Ader, Felten, Cohen 1990; Madden, Felten, Felten et al 1994; Amital, Blank, Shoenfeld 1996; Nicholson, Kuchroo 1996; Aulakh, Mazzola-Pomietto, Murphy 1996; Eilat, Mendlovic, Doron 1999; Schwarz, Chiang, Muller et al 2001; Wrona 2006; Gaykema, Chen, Goehler 2007; Witek-Janusek, Gabram, Mathews 2007) (See Table 5.1) Adequate neuropharmacolog-ical therapy should be administered to reverse the aforementioned abnormal neuroautonomic and CNS disorders

Neuroimmunological Diseases

We will refer to some diseases well investigated by our research group

Gastrointestinal DiseasesDuodenal ulcer, type B gastritis and Crohn’s disease are caused by raised levels of plasma noradrenaline, NA/Ad ratio, p5-HT, and nocturnal plasma cortisol These fi ndings fi t well with the TH-1 immunologi-cal profi le usually found in these subjects The fact that the cortisol plasma levels do not show signifi cant reduction after the dexamethasone challenges in these patients gives additional support to the postula-tions Furthermore, clonidine does not trigger growth hormone increase in duodenal ulcer patients (Jara, Lechin, Rada et al 1988; Lechin, van der Dijs, Rada

et al 1990b) These fi ndings are caused by the regulation of α-2 receptors at the hypothalamic level, which depends on the over-release of noradrenaline from the A5 axons at this level Other immunologi-cal evidence demonstrated that the gastrointestinal diseases these patients present with should be consid-ered as being caused by the TH-1 autoimmune pro-

down-fi le Conversely, patients affected by type A gastritis, gastric ulcer, ulcerative colitis, refl ux esophagitis, and gastric maltoma always showed the TH-2 immunolog-ical profi le as well as the uncoping stress neuroendo-crine and neuroautonomic disorder (Lechin, van der Dijs 1973; Lechin 1977; Christensen 1980; Lechin, van der Dijs, Jakubowicz et al 1987a; Lechin 1988b; Lechin, van der Dijs, Rada et al 1989b; Lechin, van der Dijs, Vitelli et al 1990a; Lechin 1988b)

Both the ulcerative colitis and Crohn’s disease merit some special comments The former should

be included among the TH-2 disorders whereas the latter always shows the TH-1 autoimmune disorder These postulations are supported by the successful neuropharmacological therapies prescribed for them Readers should be aware that patients with Crohn’s disease are frequently misdiagnosed because intes-tinal lesions are located at the submucosal (deep) level, nonaccessible to punch biopsy, and in addition,

the sleep disorder always present in all these patients

(Tandon, Shipley, Taylor et al 1992) Considering

that all of them show a short REM latency and

fre-quent awake periods, we prescribe a noradrenaline

and serotonin uptake inhibitor, such as doxepin

(25 mg) or imipramine (25 mg) and a noradrenaline

and serotonin– releasing agent, such as mirtazapine

This drug is an α-2 and 5-HT-2 antagonist that

trig-gers both noradrenaline and serotonin release from

NA and 5-HT axons, respectively In our long

expe-rience with the polysomnography investigation, we

found that prolongation of the SWS period parallels

clinical improvement Indeed, the short-REM latency

they always present with (before treatment) should

be attributed to the exhaustion of the A6(NA) and

DR(5-HT) nuclei This phenomenon is consistent

with the well-known fact that both the A6(NA) and

the DR(5-HT) nuclei are responsible for the SWS and

both become silent at the REM sleep stage

The sustained and progressive improvement

obtai-ned in all these patients might be monitored

through-out the clinical assessment We never observed any

type of undesirable side effects In addition, it should

be mentioned that children with ADHD reach

abso-lute and irreversible improvement in all the cases, after

long-term sustained neuropharmacological therapy

such as that we have outlined for psychotic patients

In our long experience with this issue, we found

that psychotic patients maximally improve with the

addition of a small dose of olanzapine (Dawe, Huff,

Vandergriff et al 2001) or clozapine (Youngren,

Moghaddam, Bunney et al 1994) (before bed)

These drugs excite the A6(NA) neurons (in addition

to the other effects at both DA and 5-HT neurons)

Clozapine also excites A6(NA) neurons and exerts

an α-1 antagonistic effect, which explains the deep

sleep that it provokes This fact should be taken into

account to enhance the SWS of these patients

Neuroimmunological Profi les

Uncoping stress is associated with TH-2

immunolog-ical profi le, which is caused by low CD4/CD8 ratio,

low NK-cell cytotoxicity against K-562 target cells, and

low plasma levels of TH-1 cytokines (IL-2, IL-12, IL-18,

γ-interferon) (Kopin, Eisenhofer, Goldstein 1988;

Cunnick, Lysle, Kucinski et al 1990; Felsner, Hofer,

Rinner et al 1995; Buckingham, Loxley, Christian et al

1996; Marotti, Gabrilovac, Rabatic et al 1996; Leonard,

Song 1996; Oya, Kawamura, Shimizu et al 2000;

Calcagni, Elenkov 2006; Shakhar, Rosenne, Loewenthal

et al 2006; Matsuda, Furukawa, Suzuki et al 2007)

Coping stress is associated with TH-1

immuno-logical profi le, which is caused by high CD4/CD8

ratio, high NK-cell cytotoxicity against K-562 target

cells, and high plasma levels of TH-1 cytokines (IL-2,

Table 5.1 Neuroautonomic and Immunological Profi les Underlying Some Somatic, Psychosomatic,

and Psychiatric Diseases

Adrenal/Neural Sympathetic Predominance

Neural/Adrenal Sympathetic Predominance

References

Central pathways activated A6(NA), DR(5-HT), C1(Ad) A5(NA), MR(5-HT) Anisman 1978

Lechin et al 1996a, 2006a Peripheral pathways activated Thoracic sympathetic chain

and adrenal gland—raised plasma adrenaline and cortisol

or serotonin

↓

Lumbar sympathetic chain—raised plasma noradrenaline

↓

Burchfi eld 1979 Kvetnansky et al 1977 Jacobs et al 1981 Engeland 1998;

Lechin et al 1996a, 2006a

(TH-2)

Endogenous Depression (TH-1)

Cardiovascular disorders

Lechin, van der Dijs 2006a

Respiratory disorders

Lechin et al 1996f, 1998b; Lechin et al 2002f, 2004h

Lechin, van der Dijs 2005b

Loewy, Haxhiu 1993 Lechin, van der Dijs 2004b

Lechin, van der Dijs 2007b

Lechin et al 1994c

Sandborn et al 2001 Granulomatous colitis

(Crohn’s disease)

X Lechin et al 1988a;

Lechin et al 1989a

Lechin et al 2005c;

Lechin, van der Dijs 2005c

Lechin et al 2005d

(Continued)

Table 5.1 Continued

(TH-2)

Endogenous Depression (TH-1)

References

Hematological disorders

Immune-mediated injury

Mantzoukis 2006

Endocrinological syndromes

Lechin, van der Dijs 2006b Type 1 postprandial

(mammary and ovarian cysts)

Oliveira et al 2000

Psychiatric diseases

Lechin et al 1995a, 1996a

Craven et al 2005

Uncoping stress: Adrenal gland secretion of catecholamines (adrenaline 80%, noradrenaline 10% , and dopamine 10%) predominates over

sympathetic nerves release of catecholamines (noradrenaline 80 to 90% and dopamine 10 to 20%) Overactivity of the CNS C1(Ad) nuclei triggers excitation of the vagal (medullary) nuclei, which is responsible for the peripheral parasympathetic nerves activity Thus, alternancy

of these two ANS peripheral branches is frequently seen in patients affected by the uncoping stress syndrome (Ad.S., Adrenal stage; P.S.,

parasympathetic stage) Predominance of both adrenal and cortisol are responsible for the Th-2 immunological predominance.

Endogenous depression: Absolute predominance of neural over adrenal sympathetic activity underlies this CNS and ANS profi le (N.S.,

neural sympathetic stage) At CNS level, the A5(NA) nucleus exerts maximal inhibition of both the C1(Ad) and vagal (medullary) nuclei This CNS disorder is responsible for the disappearance of both adrenal and parasympathetic peripheral activities In addition, the inhibi- tion of the adrenocortical glands is responsible for the disinhibition of the thymus, which redunds in the TH-1 immunological profi le.

by glucocorticoids in both seropositive and ative MG patients (these latter patients do not have anti-ACh autoantibodies that can interfere at the neuromuscular junction) Hence, the myasthenic symptoms cannot be attributed to this synaptic inter-ference in seronegative MG patients.

seroneg-The greater obstacle that we found in treating these patients should be attributed to both previous steroid therapy and thymectomy Absolute recovery has been obtained in hundreds of MG patients who had not been taking steroids These drugs provoke the exhaustion of both the DR(5-HT) and the adrenal gland This disease affected Dr Lechin (12 years ago) and, he is absolutely normalized because he rejected this type of therapy, which, in our opinion, should be forbidden

Other TH-1 autoimmune diseases have been cessfully treated in our institute Multiple sclerosis, Sjögren disease, fi bromyalgia, pemphigus, sclero-derma, rheumatoid arthritis, recurrent abortions, and other TH-1 autoimmune patients are frequently referred to our institute for that purpose Several pho-tographical evidences have been published in some

suc-review articles and in our last published book (Lechin, van der Dijs, Lechin et al 2002a) In addition, cases

of Crohn’s diseases are also presented in our book, which might be a useful reference on the absolute normalization of patients who presented with these radiological disorders at the small bowel level and/or colon or stomach Special mention should be made with respect to multiple sclerosis We have success-fully treated 23 cases after the failure of β-interferon therapy to avoid the relapses always observed follow-ing the initial successes obtained with this drug Two blind patients are included among these latter cases Both of them recovered the sight that they had lost despite the β-interferon treatment

Other TH-2 autoimmune diseases such as ative colitis have been successfully treated also with

ulcer-an adequate neuropharmacological protocol that enhances the Th1/Th2 ratio Details of these proto-cols can be found in our previous published articles (Lechin, van der Dijs, Insausti et al 1982d, 1985c; Lechin, van der Dijs, Orozco 2004e, 2005c; Lechin, van der Dijs 2005c)

Hematological and Vascular Disorders

IDIOPATHIC THROMBOCYTOPENIC PURPURA AND POLYCYTHEMIA VERA We demonstrated that both idiopathic throm-bocytopenic purpura (ITP) and polycythemia vera (PV) were caused by an ED profi le (Lechin, van der Dijs, Orozco et al 2004e, 2005b) In addition, immu-nological investigation demonstrated that both syn-dromes are caused by a TH-1 autoimmune profi le

the lymphoid granulomas are located at the small

bowel rather than at the colon level That area of the

intestine is not accessible to endoscopic

investiga-tion Thus the diagnosis of Crohn’s disease should be

made according to radiological, immunological, and

neuroautonomic procedures (Lechin, van der Dijs,

Lechin et al 1989a, 2002a) With respect to this, it

should be known that patients with ulcerative colitis,

but not those with Crohn’s disease, present with

posi-tive ANCA test (antineutrophil cytoplasmic antibody)

(Sandborn, Loftus, Colombel et al 2001; Joossens,

Reinisch, Vermeire et al 2002) This test refl ects TH-2

immune profi le, which parallels the uncoping stress

disorder

Neurological Diseases

Two types of neurological diseases, the multiple

scle-rosis and the Guillian Barré syndrome, are caused by

TH-1 and TH-2 immunological disorders, respectively

(Lechin, van der Dijs, Lechin et al 2002a; Kuwabara

2007) Both of them have been successfully treated

in our institute with neuropharmacological

thera-pies to restore the immunological TH-1 versus TH-2

balance

Other neuroimmunological diseases such as

myas-thenia gravis (MG) merit some special comments

We have investigated and treated several hundreds

of these patients (Lechin, van der Dijs, Orozco et al

1996e, 1996f) The neuroimmunological

investiga-tion carried out in our institute demonstrated that

this syndrome should be considered as a TH-1

immu-nological predominant disorder Thus, exhausted

A6(NA) and DR(5-HT) nuclei would be overwhelmed

by the A5(NA) and MR(5-HT) binomial The fact

that thymectomy and/or steroid therapy is able to

suppress both the thymus gland hyperactivity and the

MR(5HT) predominance fi ts well with the benefi

-cial (short-term) therapeutic alleviation of symptoms

seen in these patients submitted to these therapies

It should be known that steroids excite the DR(5-HT)

but not the MR(5-HT) neurons, because the former,

but not the latter, is crowded by cortisol (excitatory)

receptors In addition, it should be taken into account

that steroids suppress neural sympathetic activity,

which is enhanced in all TH-1 patients The

allevi-ation of symptoms triggered by pyridostigmine, a

drug that does not cross the BBB in both

seronega-tive and seroposiseronega-tive MG patients should be

attrib-uted to the ability of this drug to excite the adrenal

gland, which is crowded by excitatory nicotine

recep-tors rather than to the direct effect of the drug at the

neuromuscular junction These glands are

underac-tive in all types of TH-1 disorders This explanation

fi ts well with the improvement of symptoms provoked

short reports on this issue; however, we are aware that practitioners would not accept this type of therapeu-tic approaches Thus, we will not discuss this issue in this chapter.

Malignant Diseases

STRESS, IMMUNOLOGY, AND CANCER: EFFECTS OF PSYCHOACTIVE

lym-phoma, myeloma multiple, and myeloid leukemia present with the TH-2 immunological profi le We published a review article in 1987 (Lechin, van der Dijs, Jakubowicz et al 1987a) We presented pho-tographic evidence showing the benefi cial results obtained with our therapeutic neuropharmacologi-cal approach aimed at normalizing the CNS and ANS neuroautonomic disorders after the administration

of an adequate neuropharmacological therapy Both neuroendocrinological and immunological disorders were also normalized through the 6 years that this protocol lasted

We measured noradrenaline, adrenaline, amine, p5-HT, f5-HT, plasma cortisol, and plasma prolactin levels both before and after monthly con-trol evaluation The immunological investigation included the assessment of the number of peripheral lymphocytes CD3, CD4, CD8, and NK-cells In addi-tion, NK-cell cytotoxicity against the K-562 target cells was also assessed periodically This therapeutic research has been carried out since 1980 up to the present (Lechin, van der Dijs, Azócar et al 1988c; van der Dijs, Lechin, Vitelli et al 1988a; van der Dijs, Lechin, Vitelli et al 1988b; Vitelli, Lechin, Cabrera

dop-et al 1988; Lechin S Vitelli, Martinez dop-et al 1988)

A total of 177 cancer patients participated in our fi rst protocol All patients had advanced cancer showing an uncoping stress profi le and had previ-ously refused chemotherapy Of the 177 advanced cancer patients, 144 (81.4%) survived for more than

5 years after the initiation of therapy In addition, the 33 remaining advanced cancer patients showed survival time that was signifi cantly longer than that supposed to be the upper limit of their lifetime expec-tancy (Table 5.2) Normalization of neurochemical, endocrinological, and immunological parameters was observed within 2 to 3 months of the initiation

of the neuropharmacological therapy (Fig 5.5) Our initial research work was presented in international meetings and in many cancer centers in the United States and other countries Some clinical reports were also published in several journals and in our last book (Lechin, van der Dijs 1982; Lechin, van der Dijs, Azócar et al 1987b; Lechin, van der Dijs, Lechin et al 1989a; Lechin, van der Dijs, Vitelli et al

1990a; Lechin, van der Dijs, Lechin 2002a, 2004d)

An anti-TH-1 neuropharmacological therapy was

successfully carried out in these patients No relapses

were observed over months and years among the 11

PV and the 13 ITP patients included in our protocol

(Lechin, van der Dijs, Orozco et al 2004e, 2005b)

Normalization (without relapses) of both the

neu-roautonomic and the immunological profi les has been

obtained in all ITP and PV patients who had received

the neuropharmacological therapy In addition,

nor-malization of the wake–sleep cycle was observed

in all these patients This latter issue merits some

comments In our long experience dealing with the

neuro-immunopharmacological investigation and

therapy, we learned that normalization of the wake–

sleep cycle is the best index of improvement We

tested this parameter in our sleep research laboratory

not only through polysomnographic assessment but

also through investigation of circulating

neurotrans-mitters (NA, Ad, DA, p5-HT, f5-HT, and tryptophan)

during both the waking state and each stage of the

nocturnal sleep cycle It should be known that

normal-ization of the sleep disorders depends on the

accom-plishment of the fi ve sleep stages that integrate the

sleep cycle: SWS-1, SWS-2, SWS-3, SWS-4, and REMs

without awakenings interruptions

THROMBOSTASIS DISORDERS These disorders are caused

by a TH-1 autoimmunological profi le Autoantibodies

against vascular endothelial cells are frequently

reported to be present in their sera These fi ndings

support the postulation that vasculitis,

cardiovascu-lar and cerebrovascucardiovascu-lar thrombostasis, and in

addi-tion, phlebothrombosis disorders are caused by the

same TH-1 autoimmune profi le In addition, we have

found that the p5-HT value is positively correlated

with blood coagulation and thus, with all thrombotic

events We demonstrated that an adequate

neuro-pharmacological therapy to enhance CNS

serotoner-gic activity (with serotonin uptake inhibitors) triggers

the parallel reduction of thrombogenesis It should

be remembered that p5-HT depletion interferes

with thrombogenesis Thus, this effect triggered by

all types of serotonin uptake inhibitors would easily

explain the interference by these drugs on all types

of thrombotic events (Lechin, van der Dijs 2004b,

2004c, 2004d; Lechin, van der Dijs, Orozco et al

2004g; Lechin, van der Dijs, Lechin 2005a; Lechin,

van der Dijs, Orozco et al 2005b) This issue led us to

treat all types of arterial and venous thrombosis by the

administration of a minimal dose of serotonin uptake

inhibitors, such as clomipramine, paroxetine,

sertra-line, etc This therapeutic strategy impedes coronary,

cerebrovascular, and any other vascular

thrombo-sis These patients have not needed any

instrumen-tal therapy to deobstruct vessels.We published some

Summarizing our long experience, we cluded that the worsening of cancer is positively correlated with uncoping stress In addition, we dem-onstrated that an adequate neuropharmacological therapy enhances both the TH-1 immunological pro-

con-fi le and the NK-cell cytoxicity against the K-562 target cells Ovarian cancer, melanoma, and mammary, pros-tate, and gastric adenocarcinomas were the most easy

to improve In addition, non–Hodgkin’s lymphoma and maltoma showed a 100% of improvement

Psychosomatic Diseases

A bulk of experimental, clinical, and therapeutic data support the postulation that the gastrointestinal and biliary systems, along with the cardiorespiratory machinery, constitute the visceral areas that maxi-mum refl ect both the physiological and pathophysi-ological oscillations of the CNS structures that integrate the pontomedullary and spinal circuitry responsible for the CNS to ANS physiological cas-cade The fact that those visceral areas are included into the more innervated structures and, in addi-tion, considering that those peripheral systems are targeted by all types of peripheral agents as well as

by psychological stressors might help understand why the visceral areas are the most frequently affected.Although we have investigated a great deal of clini-cal, physiological, and pharmacological data dealing with the cardiovascular parameters, we will refer in this chapter to a bulk of both clinical and scientifi c research fi ndings concerning to the physiological and pathophysiological interactions between gastro-intestinal and biliary systems and the CNS circuitry Peripheral assessment included biliary motility, distal colon motility, circulating neurotransmitters, clinical data, and some other parameters In addition, we will present evidence dealing with the effects of some neu-ropharmacological drugs on both neuroautonomic and visceral functioning

Finally, we will present physiological, cological, and therapeutic evidence supporting the postulation that the so-called psychosomatic diseases depend on the peripheral ANS unbalance, which refl ects on the CNS circuitry disorders Although this issue is valid for all types of diseases, we will choose some examples that might be graphically demonstrated

pharma-Irritable Bowel Syndrome and Biliary DyskinesiaClinical and pathophysiological research investiga-tions carried out in our institute (Lechin, van der Dijs, Lechin-Báez et al 1994c) demonstrated that

Furthermore, we recently sent a commentary to the

Journal of Biological Chemistry (Lechin, van der Dijs

2007c), related to a research article by Sastry et al

(2007) These authors ratifi ed our fi ndings dealing

with the positive correlation found between

malig-nancy and adrenaline plasma levels as well as the

neg-ative correlation between the former parameters and

NK-cell cytotoxicity

Up to the present, we have successfully treated

more than 1000 advanced cancer patients who rejected

both chemotherapy and radiotherapy, because those

patients were aware that both therapeutic procedures

destroy the immune system

Table 5.2 Follow-up of 177 Advanced Cancer Patients

Submitted to Neuropharmacological Therapy

Adapted from the Archivos Venezolanos de Farmacologia Clinica

y Terapeutica (Lechin et al 1987b).

A total of 177 advanced cancer patients treated by

neuropharmaco-logical therapy: 5 patients survived after 6 years, 7 patients survived

after 5 years, 13 patients survived after 4 years, 21 patients survived

after 3 years, 24 patients survived after 2 years, 42 and patients

sur-vived after 1 year All patients had metastatic tumors and began

neuropharmacological therapy during exacerbation periods All

patients began neuropharmacological therapy immediately after

partial or total removal of primary tumor None them showed

further exacerbation periods.

were experimentally triggered by the same pharmacological manipulation Even more, we found that mianserine, a serotonin-releasing agent at CNS level, was able to revert both the sigmoidal hypertony and the biliary dyskinesia (Fig 5.6).

neuro-In summary, we found that both ANS disorders (colonic and biliary) refl ected a common CNS abnor-mality that allows us to postulate that both spastic colon and biliary dyskinesia were triggered by hyper-neural sympathetic activity (at the peripheral level) and by A5(NA) and MR(5-HT) overactivity at the CNS level (Lechin, van der Dijs 1979b, 1979c, 1979d, 1979e, 1981a; Lechin, van der Dijs, Gómez et al 1982a, 1982a, 1982c, 1982c; Lechin, van der Dijs 1983; Lechin 1992b) However, this CNS and neuroauto-nomic preponderance was reverted to the opposite phase during the diarrheic period: low sigmoidal tone, rectal hypermotility, and biliary hypermotility

At this period a C1(Ad) and DR(5-HT) predominance over A5(NA) and MR(5-HT) would be underlying this clinical syndrome (Lechin, van der Dijs, Bentolila

et al 1977b; Lechin, van der Dijs 1981d, 1981e; Lechin, van der Dijs, Acosta et al 1983b; Lechin 1992b)

CNS Circuitry Involved in Distal Colon Motility and Biliary Disorders

We demonstrated that both high sigmoidal tone and gallbladder hypokinesia are frequently associated

there exist two types or two faces of the so-called

irri-table bowel syndrome (IBS): the spastic colon and

the nervous diarrhea Periodical alternation of these

two clinical stages is the rule High sigmoidal tone and

low rectal activity are seen during the spastic colon

periods whereas low sigmoidal tone and high rectal

motility are seen during the latter period (Lechin,

Jara, Rada et al 1988a, 1988; Cabrera, van der Dijs,

Jimenez et al 1988; Lechin, van der Dijs, Lechin-Báez

et al 1994c) In addition, biliary dyskinesia is

fre-quently seen during the spastic but not the diarrheic

period Gallbladder emptying was triggered neither

by the Boyden test meal (eggs, milk, butter) nor by

the intravenous administration of CCK during the

spastic colon period Furthermore, it has been also

demonstrated that dihydroergotamine (an α-2

antag-onist) was able to interfere with the cholecystokinetic

effect of the intravenously injected CCK to both

nor-mal subjects and diarrheic patients (Lechin, van der

Dijs, Bentolila et al 1978; Lechin, van der Dijs 1979b;

Lechin, van der Dijs, Orozco et al 2002b; Lechin,

van der Dijs 2007b) Finally, this drug was also able

to enhance the sigmoidal tone of both normal and

diarrheic subjects signifi cantly (Lechin, van der Dijs,

Bentolila et al 1977a, 1977b; Lechin, van der Dijs

1983, 2007a) In summary, it was found that both the

spastic colon syndrome and the biliary dyskinesia

were frequently associated in the same patients and,

furthermore, that both types of motility disorders

700 600 500 400 300 200 100

Posttreatment monthly periods

Plasma adrenaline ( ) pg/mL Plasma cortisol ( ) ng/mL

0

Figure 5.5 A total of 177 advanced cancer patients received neuropharmacological therapy instead of chemotherapy They were followed

up for 6 years or more All of them showed signifi cant improvement Absolute disappearance of tumors was seen in 144 patients ers), whereas signifi cant improvement and increased survival time expectancy was seen in the other 33 patients (nonresponders) All patients showed increased levels of epinephrine, epinephrine over norepinephrine (E/NE) plasma ratio, and low levels of natural killer (NK) cell cytoxicity against the K-562 target cells Absolute normalization of neuroimmunological parameters was seen in all responders Adapted from Archivos Venezolanos de Farmacologia Clinica y Terapeutica (Lechin, van der Dijs, Azócar et al 1987b) This conference was lectured by invitation at the XI Congress of the Latinoamerican Association of Pharmacology and the II Congress of the Interamerican Society for Clinical Pharmacology and Therapeutics, Buenos Aires, Argentina, November 1986, and by invitation at the following centers: The University of Texas, MD Anderson Cancer Center; Arthur James Cancer Center (Iowa); National Cancer Institute (Maryland); University

(respond-of South Florida (Tampa); The Ohio State University, Columbus, 1992

in those patients with IBS during the colon spastic

phase These patients frequently report postprandial

abdominal pain at the right hypochondria and/or

hypogastria, as well as constipation No gallbladder

emptying after the Boyden test meal or the

intrave-nously injected cholecystokinin is also frequently

observed in these subjects when they are submitted

to these challenges Furthermore, it has been

demon-strated that both biliary and sigmoidal disorders can

Figure 5.6 High sigmoidal tone in a patient affected by the

“spas-tic colon” syndrome, who also showed hypokine“spas-tic gallbladder

(no emptying after the Boyden test meal) Mianserine (an α-2 and

serotonin-2 antagonist), which enhances the release of serotonin

from CNS serotonergic neurons reduced the sigmoidal tone and

eliminated abdominal pain The enhanced rectal activity

pro-voked by mianserine should be attributed to the α-2 antagonist

activity exerted by the drug Clonidine, an α-2 agonist suppresses

rectal activity and augments sigmoidal tone A second oral

chole-cystography (X-ray), performed 7 days after a therapeutic trial

with mianserine (15 mg, daily), was enough to normalize the

gall-bladder emptying and to eliminate spastic colon symptoms.

Figure 5.7 Distal colon motility carried out in a normal

sub-ject showed low sigmoidal tone and no phasic activity (waves)

Mianserine (an α-2 antagonist and serotonin-2 antagonist)

enhanced phasic activity at the sigmoidal but not rectal

seg-ment Clonidine, an α-2 agonist, suppressed both the abdominal

pain and the increased sigmoidal activity provoked by

mianser-ine These fi ndings are consistent with the demonstrated fact

that the sigmoidal segment is heavily innervated by the

myen-teric plexa, which includes serotonergic neurons and NA nerves

Parasympathetic nerves cooperate with the former and

antago-nize the latter neurological activities.

100 0 100 0

100

A

B

0 100 0

20 minutes

Low intestinal tone

High intestinal tone mmHg

Figure 5.8 (A) Patient with irritable bowel syndrome (investigated

during diarrheic period) He showed low sigmoidal tone and raised rectal activity In addition, this patient had normal gallbladder emptying when tested with an intravenous dose of cholecystokinin (CCK) Administration of dihydroergotamine (DHE, an α-2 antag- onist) (6 mg intramuscularly injected) suppresses diarrhea and increased both sigmoidal and rectal tone (more than 100 mmHg)

At the same time, DHE interferes with the CCK-induced gall bladder emptying The DHE injection also provoked abdominal pain (B) Patient with irritable bowel syndrome (investigated during the constipation period) Abdominal pain was exacerbated during postprandial periods High sigmoidal tone was demonstrated dur- ing the distal colon motility investigation (more than 100 mmHg) Cholecystokinin intravenously injected was not able to provoke gallbladder emptying and in addition, triggered abdominal pain

at both right hypochondrium and hypogastrium Mianserine (an α-2 and serotonin-2 antagonist) orally administered, was able to reduce sigmoidal tone and increase rectal phasic activity (waves) Gallbladder emptying was normalized by the drug Abdominal pain was also relieved However, further administration of intra- muscular clonidine (0.15 mg), an α-2 agonist, increased sigmoidal tone and provoked abdominal pain.

be experimentally induced by the administration of centrally acting α-2 antagonists to normal subjects (such as dihydroergotamine, yohimbine, regitine, mianserine) (Figs 5.7, 5.8, and 5.9) These fi ndings allowed us to postulate that these drugs provoked

by acting at the CNS level Considering that both the C1(Ad) and the A5(NA) nuclei are crowded

by α-2 inhibitory autoreceptors, both α-2agonists and α-2antagonists would act at those CNS nuclei (Li, Wesselingh, Blessing 1992; Lechin 1992b; Lechin, van der Dijs, Orozco 2002b; Lechin, van der Dijs, Lechin 2002c; Fenik, Davies, Kubin 2002; Lechin, van der Dijs 2007b) Furthermore, considering that other experimental evidence demonstrating that clonidine,

an α-2 agonist, was able to antagonize the effects voked by dihydroergotamine reinforced our postula-tions Summarizing and taking into account that both

pro-Lechin, van der Dijs, Lechin et al 1989a, 1994a, 1996c; Lechin, van der Dijs, Orozco et al 1996d, 1996e) Finally, tthe fact that clinical, neurochemical, and distal colon motility disorders were normalized by an adequate neuropharmacological therapy addressed

to enhance neural sympathetic activity supports our postulation This therapy included a small dose of buspirone (5 mg) before breakfast and lunch (this serotonin-1A agonist triggers the inhibition of the overactive DR(5-HT) neurons) In addition, a small dose of doxepin (25 to 50 mg) or imipramine (25 mg) before supper and a small dose of mirtazapine (15 to

30 mg) before bed should be administered to these patients This treatment triggered normalization of both clinical and neuroautonomic parameters within the fi rst few (3 to 4) weeks Normalization of the sleep cycle paralleled the clinical improvement (Lechin, van der Dijs, Lechin et al 1989a; Lechin, van der Dijs, Jara et al 1997c, 1998a)

The fi ndings summarized in this chapter allow one to understand why medical knowledge should not

be divided into fractions, and in addition, why only

an adequate integration of physiological, ological, and pharmacological knowledge is required for the right understanding of the clinical syndromes, which enables formulation of adequate therapeutic strategies

pathophysi-We will offer a highly experimental and tive example to the readers We demonstrated that dogs subjected to captivity (median raphe stressor agent) presented with glucose intolerance (insulin resistance) within 5 to 7 days after the restraint stress (Lechin, van der Dijs, Lechin 1979b) In addition, these dogs also showed the spastic colon syndrome when tested using distal colon motility procedure Signifi cant increases of p5-HT levels were observed

illustra-A5(NA) and C1(Ad) nuclei interchange inhibitory

axons (Li, Wesselingh, Blessing 1992), both α-2

antag-onists and α-2 agonists would be able to reverse both

types of physiological and pathophysiological

pre-dominance by acting at those nuclei (Lechin, van der

Dijs, Bentolila et al 1977a, 1977b, 1978; Lechin, van

der Dijs 1979b, 1983; Lechin 1992b; Lechin, van der

Dijs 2008; Lechin, van der Dijs, Orozco 2002b; Lechin,

van der Dijs 2007b; Lechin, van der Dijs 1981d) The

fact that C1(Ad) and (A5)NA predominance

under-lie both the uncoping stress and the ED syndromes,

respectively, allowed us to think that the

gastroin-testinal disorders discussed should be considered as

peripheral symptoms refl ecting CNS

pathophysiologi-cal disorders Finally, this postulation received

addi-tional support by the demonstration that an adequate

neuropharmacological therapy was able to normalize

both gastrointestinal and psychological syndromes

Patients with IBS show periodical alternation of

constipation and diarrhea Low sigmoidal tone and

rectal hypermotility were found during diarrheic

peri-ods, whereas high sigmoidal tone and rectal

hypoac-tivity was observed during spastic periods Circulating

neurotransmitter assessment demonstrated that the

noradrenaline/adrenaline ratio and p5-HT levels are

signifi cant lowered during the diarrheic periods, at

which time f5-HT is signifi cantly increased (because

of platelet aggregability) This last parameter always

showed close positive correlation with adrenaline and

cortisol plasma levels (at morning periods) In

accor-dance with this observation, we postulated that the

uncoping stress disorder was responsible for the

diar-rheic syndrome The fact that signifi cant positive

cor-relations have been found among adrenaline, f5-HT,

and cortisol at these periods reinforced our point of

view (Lechin, van der Dijs, Jakubowicz et al 1987a;

Figure 5.9 Low sigmoidal tone and normal

gallbladder emptying after the Boyden test

meal (AII and BII) was reverted by high

sigmoi-dal tone and no gallbladder emptying (AIV and

BIV) after 7 days of dihydroergotamine

admin-istration (an α-2 antagonist), 2.5 mg three

times daily Symptoms of spastic colon

(con-stipation and abdominal pain) were observed

at this period.

d-amphetamine, which are able to deplete CNS and

distal colon serotonin stores, were also able to reduce both sigmoidal spasticity and depressive symptoms Our fi ndings ratifi ed others by Gershon and Bursztajn (1978), who demonstrated that serotonin neurons located at the myenteric plexa level are protected, isolated from the peripheral blood by the hemato–myenteric barrier This hemato–myenteric barrier would be similar to the BBB and thus, would inter-fere with the direct cross talk between the myenteric plexa and blood stream Thus, these 5-HT neurons should be considered as belonging to the CNS This presumption is supported by our fi ndings showing that p5-HT values are signifi cantly reduced during the diarrheic periods (lowered sigmoidal tone and reduced noradrenaline/adrenaline plasma ratio), which afforded defi nite support to our point of view.Other studies carried out by our research group demonstrated that spastic colon patients present

a depressive profi le frequently The frequent ciation between these clinical syndromes and EH and the TH-1 autoimmune profi le, which has been reported by us and many other authors, should also

asso-be considered (Lechin, van der Dijs, Bentolila et al 1977a, 1977b, 1978, 1981d; Lechin, van der Dijs 1979b, 1981a, 1982; Lechin, van der Dijs, Gómez et al 1982a, 1982c; Lechin, van der Dijs 1983; Lechin, van der Dijs, Gómez et al 1983a; Lechin, van der Dijs, Acosta

et al 1983b; Lechin, van der Dijs, Jakubowicz et al 1985a, 1985b; Lechin, van der Dijs, Vitelli et al 1990a; Lechin 1992b; Lechin, van der Dijs, Lechin-Báez et al 1994c; Lechin, van der Dijs, Orozco 2002b; O’Brien, Lamb, Muller et al 2005; Ladep, Obindo, Audu et al 2006; Cole, Rothman, Cabral et al 2006; Kurland, Coyle, Winkler et al 2006; Masuko, Nakamura 2007; Radziwillowicz, Gil 2007; North, Hong, Alpers 2007; Liebregts, Adam, Bredack et al 2007; Lechin, van der Dijs 2007a, 2007b) Thus, clinicians should try

to understand that the fragmentation of the truth withdraws doctors from the right way to diagnose and treat patients

Summarizing, we quoted evidence which onstrates that both spastic colon and spastic biliary sphincter are caused by the same neuroautonomic disorder Our fi ndings showing that an α-2 and 5-HT-2 antagonist drug (mianserine) is able to antagonize both higher sigmoidal tone and rectal phasic hypoactivity, and in addition, allows the gall-bladder emptying induced by CCK, indicates that both the sphincter of Oddi and the sigmoidal– rectal sphincter are positively correlated with the neu-ral sympathetic activity Furthermore, considering that both mianserine and fenfl uramine, two sero-tonin releasing agents, were able to revert both the colonic and the biliary disorders allows assigning a primordial role to the serotonergic neurons located

dem-at this period Furthermore, dogs became apdem-athetic,

neither barked, nor showed the normal responses

to the environmental stimuli For instance, they did

not react to aggression by other dogs or to children’s

caresses At that time we ignored that serotonin is

positively correlated with MR(5-HT) activity and that

restraint stress excites MR(5-HT) but not DR(5-HT)

neurons Finally, the fact that these dogs showed also

enhanced neural sympathetic and reduced adrenal

sympathetic activities as revealed by the plasma

nor-adrenaline/adrenaline ratio demonstrated that the

A5(NA) and MR(5-HT) predominance underlies

not only depression but also the insulin resistance

and the spastic colon syndromes (Lechin, van der

Dijs, Hernandez-Adrian 2006a; Lechin, van der Dijs

2006a, 2006b)

We will add some comments on the CNS and

peripheral serotonergic mechanisms involved in the

IBS We have investigated hundreds of these patients

during both the spastic colon and the diarrheic

peri-ods We found that raised noradrenaline and p5-HT

and lowered adrenaline levels caused the spastic

phase whereas predominant adrenaline levels over

noradrenaline, low p5-HT levels, raised f5-HT levels,

and increased platelet aggregability were observed

during the diarrheic periods In addition, we also

found that whereas plasma cortisol levels (at morning)

increased in diarrheic patients (when compared with

spastic patients) the opposite profi le was observed

with respect to prolactin plasma levels This hormone

was found to be much more increased in spastic than

in diarrheic patients Considering that this parameter

is positively correlated with the MR(5-HT) activity, we

assumed that the neuroendocrine disorder described,

which underlies the spastic colon syndrome, should

be associated to the ED syndrome We quoted a great

deal of evidence that allowed postulating that this

psy-chological syndrome would depend on the

predomi-nance of the MR(5-HT) and A5(NA) binomial over

the C1(Ad), A6(NA), and DR(5-HT) CNS circuitry

Conversely, predominance of the latter circuitry

would underlie the uncoping stress disorder (Lechin,

van der Dijs 2006a, 2006b, 2007a)

Additional experimental evidence that emanated

from our research work allows the understanding that

the sigmoidal tone depends on the serotonergic

neu-rons located between the two muscular intestinal

lay-ers and that this neuronal system should be considered

as part of the CNS rather than as a peripheral nervous

system structure; thus, these serotonergic neurons

should react in parallel with some CNS serotonergic

circuitry This issue should be associated also with the

concept of the “brain-gut axis” that we introduced

in 1977 (Lechin, van der Dijs, Bentolila et al 1977b;

Lechin, van der Dijs, Gómez et al 1982c, 1983a) In

support we demonstrated that both fenfl uramine and

Additional fi ndings showed that f5-HT plasma levels were negatively correlated with FEV1 (forced expiratory volume in one second) This fi nding led

us to think that reducing the concentration of f5-HT

in plasma may be useful in treating patients during acute periods

at the myenteric plexus of the Auerbach Axons of

these neurons innervate and excite the longitudinal

(external) muscle layer and are responsible for the

intestinal tone Furthermore, taking into account a

bulk of experimental and clinical data, it is possible

to postulate the parallelism between both the CNS

and the peripheral ANS

BRONCHIAL ASTHMA

This syndrome should be considered as a two-faced

coin, the symptoms of which would depend on the

CNS physiological disorder period An uncoping

stress profi le underlies acute asthma attacks whereas

a “major depression” CNS circuitry is detected during

nonacute periods In addition, both TH-2 and TH-1

immunological profi les parallel both syndromes,

respectively

Asthma attacks are caused by raised levels of

plasma adrenaline and f5-HT whereas, predominant

levels of noradrenaline and p5-HT are found during

nonattack periods Increased platelet aggregability

would be responsible for the f5-HT peaks, because

these both disorders are closely positively correlated

with plasma adrenaline values, observed during

asthma attacks (Lechin, van der Dijs, Lechin et al

1994a, 1996c; Lechin, van der Dijs, Orozco et al

1996f; Lechin A Varon, van der Dijs et al 1994)

Dissociation of the two ANS peripheral branches

is also observed at those two periods of bronchial

asthma disease Thus, adrenal sympathetic and

neu-ral sympathetic branches are positively correlated

with the acute and nonacute asthma periods,

respec-tively (Fig 5.10)

Considering that adrenergic activity triggers

bron-chial dilatation, whereas bronbron-chial spasms depend

on neural sympathetic activity (Salonen Webber SE,

Widdicombe 1990) some other pathophysiological

mechanisms should be invoked in order to explain

this apparently contradictory phenomenon

Acute Periods

We demonstrated (Lechin, Varon, van der Dijs et al

1994) that both plasma catecholamines (adrenaline,

noradrenaline and dopamine) and plasma

indola-mine (serotonin f5-HT) but not (p5-HT) were raised

during asthma attacks In addition, we also found that

the f5-HT plasma levels were positively and negatively

correlated with clinical severity and pulmonary

func-tion, respectively (Lechin, van der Dijs, Orozco et al

1996f) In addition, we demonstrated that plasma

cortisol was also raised during acute but not at the

Sympathetic nerve α1

α1

ACh ner ve

Figure 5.10 Peripheral neuroautonomic factors involved in

bronchial physiological and pathophysiological mechanisms Postsynaptic parasympathetic nerves contract muscular fi bers

by releasing acetylcholine (ACh) at nicotine receptors located at bronchial level Plasma adrenaline (Ad) antagonizes this effect

by acting at β-adrenergic receptors located the same lar (bronchial) level Plasma serotonin (f5-HT) is taken up by the pulmonary neuroendocrine cells (PNEC) These cells are excited and release serotonin during parasympathetic excita- tion Both ACh and serotonin cooperate to contract the bron- chial tubes during parasympathetic overactivity (sleep periods and/or over-release of histamine from excited mast cells) These bronchoconstrictor mechanisms are favored by the low adre- nal glands activity seen in both asthmatic children and old sub- jects Maximal noradrenaline/adrenaline plasma ratio is always observed in both types of patients (neural sympathetic over adrenal sympathetic predominance) Furthermore, sympathetic nerves excite parasympathetic nerves by acting at α-1 recep- tors located at the latter At the central nervous system (CNS) level, this peripheral autonomic disorder depends on the over- whelming inhibitory effects exerted by A5(NA) axons over the Cl(Ad) medullary nuclei These pathophysiological mechanisms are consistent with the abrupt suppression of asthma attacks triggered by a small dose of tianeptine (which enhances the serotonin uptake) during these acute periods However, preven- tive therapeutic approach should be addressed to the reduction

muscu-of the overwhelming neural sympathetic activity This target

is reached through neuropharmacological manipulation able

to enhance the A6(NA) activity This nucleus sends inhibitory axons to the A5(NA) neurons.

Lechin, van der Dijs, Lechin et al 2002e, 2003) This drug will reduce f5-HT plasma levels and thus, will interfere with the pulmonary vasoconstrictor effect provoked by the excess of serotonin at the vascular pulmonary area However, this drug should be admin-istered during acute periods only.

Other neuropharmacological strategies might

be used to treat asthma patients, during nonacute periods In our long experience obtained from the treatment of more than 10,000 asthmatic patients,

we found that a small dose of doxepin (10 mg) before bed is able to prevent asthma attacks, after the fi rst

3 weeks of administration of this drug Other adrenaline and serotonin uptake inhibitors, such as imipramine might be administered instead of dox-epin Absolute inhibitors of noradrenaline or seroto-nin uptake should not be used

nor-It has been shown that serotonin can induce choconstriction by an effect on presynaptic neuronal 5-HT-3 receptors located at the parasympathetic gan-glia (Fozard 1984) In addition, free- but not p5-HT is able to stimulate 5-HT-3 receptors, which crowd the medullary AP located outside the BBB (Reynolds, Leslie, Grahame-Smith et al 1989) Thus, any rise of f5-HT would provoke the parasympathetic cascade (Bezold Jarisch refl ex) responsible for nocturnal asthma attacks (Lechin 2000)

bron-Other fi ndings showed that serotonin is actively transported by the PNEC, where it is metabolized by the MAO enzyme (Strum, Junod 1972) In addition, Colebatch et al (1966) demonstrated that serotonin causes constriction of both central and peripheral airways when given to vagotomized cats and other mammals Thus, plasma serotonin is able to trigger asthma attacks both directly and/or mediated by para-sympathetic nerves Furthermore, in man, serotonin

is concentrated in platelets and is released when lets aggregate This occurs during stress situation and

plate-is also observed in immunological dplate-iseases (Hechtman, Lonergan, Staunton et al 1978; Capron, Joseph, Ameisen et a1 1987; Cazzola, Matera, Gusmitta et al 1991; Freitag, Wessler, Racke 1997) Finally, in human airways, considering that serotonin is localized at nerve terminals in the so-called PNEC (Lauweryns, van Rast 1988) and may be released upon exposure to local airway under conditions such as hypoxia, hyperoxia, and hypercapnia (Keith, Will 1982; Moosavi, Smith, Heath et al 1973), this indoleamine can exert a direct bronchoconstrictor effect (Strum, Junod 1972)

Pulmonary neuroendocrine cells are granulated epithelial cells and can be detected throughout the lung from the trachea to the alveoli (Johnson, Georgieff 1989) This PNEC is the presynaptic ele-ment and the nerve vagal ending is the postsynaptic element (Levitt, Mitzner 1989)

Bronchoconstriction evoked by serotonin involves vagal afferent nerves and is inhibited by atropine

On the basis of these fi ndings, we might

under-stand how and why plasma serotonin may provoke

asthma attacks during both acute (diurnal) active

waking periods and during (nocturnal) quiet

wak-ing and sleep periods Adrenaline-induced platelet

aggregability allows the dispersion of serotonin to

the plasma during diurnal periods whereas the

noc-turnal enhancement of plasma ACh, which interferes

with the serotonin uptake by platelets, would provoke

the f5-HT rise during sleep periods (Lechin 2000;

Lechin, van der Dijs, Lechin et al 2002e; Lechin,

Pardey-Maldonado, van der Dijs et al 2004a; Lechin,

van der Dijs, Lechin 2004b, 2005a, 2007; Lechin, van

der Dijs 2005b)

In addition, it should be known that pulmonary

vascular preparations always contract also in response

to serotonin (Hechtman 1978; Webber, Salonen,

Widdicombe et al 1990) These fi ndings allow

under-standing why serotonin plays also a primary role into

the pathophysiological mechanisms, which underlie

pulmonary hypertension (Lechin, van der Dijs 2001,

2002; Lechin, van der Dijs, Lechin et al 2002e, 2002f,

2002g, 2005a; Eddahibi, Adnot 2006) We will refer to

this subsequently

Neuropharmacological Therapy

Tianeptine enhances the uptake of serotonin from

the synaptic cleft by the serotonergic axons Taking

into account that 5-HT axons from the medullary

nuclei raphe obscurus, RM, and raphe pallidus release

serotonin at the medullary respiratory center, which

includes the C1, C2, and C3(Ad) and other

medul-lary nuclei (Kumaido 1988; Holtman, Marion, Speck

1990) it is understandable why this neurotransmitter

plays a primary excitatory role at this CNS nuclei

com-plex (Strum, Junod 1972; Fozard 1984; Lauweryns,

van Rast 1988; Reynolds, Leslie, Grahame-Smith et al

1989; Johnson, Georgieff 1989; Richard, Stremel 1990;

Arita, Ochiishi 1991; Colebatch, Olsen, Nadel 1966;

Lalley, Benacka, Bischoff et al 1997; Pan, Copland,

Post, Yeger et al 2006) In addition, serotonin stored

and further released from pulmonary

neuroendo-crine cells (PNEC) triggers bronchoconstriction;

thus tianeptine should interfere at this circumstance,

also It suppresses sudden asthma attacks However,

it should not be administered during remission

peri-ods, because it also acts at the CNS level It should be

known that tianeptine enhances the uptake of

sero-tonin by axons of active but not inactive serotonergic

neurons (Lechin, van der Dijs, Lechin et al 1998b;

Lechin, van der Dijs, Orozco et al 1998c; Lechin, van

der Dijs, Lechin 2002f, 2004f; Lechin 2005; Lechin,

van der Dijs, Hernandez 2006b)

Tianeptine may be used to improve pulmonary

hypertension also (Lechin, van der Dijs 2001, 2002;

parasympathetic activity (Haxhiu, Rust, Brooks et al 2006) Acetylcholine released to the plasma inter-feres with the platelet uptake and is responsible for the increase of f5-HT (Lechin, van der Dijs, Orozco

et al 1996f) The low levels of plasma adrenaline but not of noradrenaline observed at these periods favors the bronchoconstriction triggered by f5-HT Predominance of the noradrenaline/adrenaline ratio

is always observed in asthmatic subjects and is caused

by neural sympathetic over adrenal sympathetic predominance (Lechin, van der Dijs, Lechin et al 2004h)

CNS LevelBoth the RO and the RP serotonergic nuclei excite the medullary parasympathetic (ACh) nuclei respon-sible for the excitation of the peripheral parasym-pathetic activity (Haxhiu, Jansen, Cherniack et al 1993) Conversely, the RM-5-HT nucleus cooperates with the A5(NA) nucleus, which is responsible for the neural sympathetic activity (Richard, Stremel 1990) The A5(NA) nucleus interchanges inhibitory axons with the Cl(Ad) medullary nuclei, which send excitatory polysynaptic drive to the adrenal glands (adrenal sympathetic activity) (Lindsey, Arata, Morris

et al 1998; Lalley, Benacka, Bischoff et al 1997) Exercise-induced asthma attacks depends on the overactivity of the latter CNS circuitry: RM(5-HT)–Cl(Ad) However, considering that the plasma level of adrenaline but not noradrenaline reaches minimal level during sleep periods, nocturnal asthma attacks should be associated with both neural and parasympa-thetic but not adrenal sympathetic activity (Kumaido 1988; Li, Wesselingh, Blessing 1992; Lima, Souza, Soares et al 2007) These fi ndings fi t well with oth-ers, showing that asthma in children is always caused

by neural sympathetic predominance This minance is the profi le always seen in old patients affected by the obstructive sleep apnea syndrome (OSAS) In addition, parasympathetic predomi-nance seen during sleep periods is responsible for the raised plasma levels of acetylcholine, which enhances f5-HT plasma levels Finally, the overwhelming neu-ral sympathetic over adrenal sympathetic predomi-nance observed in both asthmatic and OSAS patients may explain the overexcitation of parasympathetic nerves, which contract bronchial structures The β-adrenergic dilatator effect of plasma adrenaline is not enough to attenuate this bronchoconstriction.Summarizing, both nocturnal asthma attacks and OSAS depend on the predominance of neu-ral sympathetic over adrenal sympathetic activity (Li, Wesselingh, Blessing 1992), whereas exercise-induced asthma attacks depend on the serotonin released because of the platelet aggregation (Lechin, van der Dijs, Orozco et al 1996f), which cooperates

predo-(Islam, Melville, Ulmer 1974) These fi ndings are

con-sistent with other observation that inhaled serotonin

induces an acute fall in lung function (greater than

20% in FEV1) in asthmatic patients but not in normals

(Tonnesen 1985; Cushley, Wee, Holgate et al 1986)

The fact that nocturnal asthma attacks are

associ-ated with increased parasympathetic activity should

be added to other fi ndings, which show that this

activity releases serotonin from intestinal source

and provokes an increase of blood serotonin (Tobe,

Izumikawa, Sano et al 1976) In addition,

hyperpara-sympathetic activity (as occurs during sleep and

post-prandial periods) interferes with p5-HT uptake, which

redounds in an increase of plasma serotonin (Rausch,

Janowsky, Risch et al 1985; Skaburskis, Shardonofsky,

Milic-Emili et al 1990)

CNS and Peripheral ANS Interactions

PERIPHERAL LEVEL Parasympathetic nerves release ACh

from terminals, which contracts bronchial structures

by acting at nicotine receptors located at the

bron-chial muscles (Haxhiu, Jansen, Cherniack et al 1993;

Hadziefendic, Haxhiu 1999; Jordan 2001) This effect

is potentiated by serotonin released at this level from

the PNEC These cells are located at ACh nerves and

serotonin is coreleased with acetylcholine during

para-sympathetic activation These neuroendocrine

struc-tures are able to uptake serotonin from the plasma;

thus, any increase of plasma 5-HT enhances PNEC

stores and is further released during parasympathetic

excitation (Pan, Yeger, Cutz 2004; Pan, Copland, Post

et al 2006)

NA sympathetic nerves excite parasympathetic

nerves by acting at α-1 receptors located at these

ter-minals (Haxhiu, Kc, Neziri et al 2003; Haxhiu, Kc,

Moore et al 2005) Conversely, plasma adrenaline

triggers bronchial dilatation by acting at β-adrenergic

receptors located at muscular fi bers, which are

pro-vided with β-adrenergic receptors (Larsson, Carlens,

Bevegard et al 1995) Thus, any predominance of

parasympathetic or neural sympathetic activity would

result in bronchial contraction Both plasma

seroto-nin and plasma histamine also trigger bronchial

con-traction by acting directly at the bronchial muscular

layer (Larsson, Carlens, Bevegard et al 1995; Kinkead,

Belzile, Gulemetova 2002)

Asthma Attacks

Asthma attacks may be triggered by both exercise

(diurnal) and sleep (nocturnal) periods The former

is associated with the rise of plasma serotonin

trig-gered by platelet aggregation, which releases

seroto-nin Platelet aggregation is triggered by the increase

of adrenaline from the adrenal glands during

exer-cise The nocturnal attack should be associated with